Compounds

ABSTRACT

The invention relates to novel imidazopyridine derivatives which are inhibitors of the transforming growth factor, (“TGF”)-β signalling pathway, in particular, the phosphorylation of smad2 or smad3 by the TGF-β type I or activin-like kinase (“ALK”)-5 receptor, methods for their preparation and their use in medicine, specifically in the treatment and prevention of a disease state mediated by this pathway.

This invention relates to novel imidazopyridine derivatives which areinhibitors of the transforming growth factor, (“TGF”)-β signallingpathway, in particular, the phosphorylation of smad2 or smad3 by theTGF-β type I or activin-like kinase (“ALK”)-5 receptor, methods fortheir preparation and their use in medicine, specifically in thetreatment and prevention of a disease state mediated by this pathway.

TGF-β1 is the prototypic member of a family of cytokines including theTGF-βs, activins, inhibins, bone morphogenetic proteins andMüllerian-inhibiting substance, that signal through a family of singletransmembrane serine/threonine kinase receptors. These receptors can bedivided into two classes, the type I or activin like kinase (ALK)receptors and type II receptors. The ALK receptors are distinguishedfrom the type II receptors in that the ALK receptors (a) lack theserine/threonine rich intracellular tail, (b) possess serine/threoninekinase domains that are very homologous between type I receptors, and(c) share a common sequence motif called the GS domain, consisting of aregion rich in glycine and serine residues. The GS domain is at theamino terminal end of the intracellular kinase domain and is criticalfor activation by the type II receptor. Several studies have shown thatTGF-β signaling requires both the ALK and type II receptors.Specifically, the type II receptor phosphorylates the GS domain of thetype I receptor for TGF-β, ALK5, in the presence of TGF-β. The ALK5, inturn, phosphorylates the cytoplasmic proteins smad2 and smad3 at twocarboxy terminal serines. The phosphorylated smad proteins translocateinto the nucleus and activate genes that contribute to the production ofextracellular matrix. Therefore, preferred compounds of this inventionare selective in that they inhibit the type I receptor and thus matrixproduction.

Surprisingly, it has now been discovered that a class of novelimidazopyridine derivatives function as potent and selective non-peptideinhibitors of ALK5 kinase.

According to a first aspect, the invention provides a compound offormula (I), a pharmaceutically acceptable salt, solvate or derivativethereof:

wherein

-   -   X is N or CH;    -   R¹ is selected from hydrogen, C₁₋₆alkyl, C₁₋₆alkenyl,        C₁₋₆alkoxy, halo, cyano, perfluoro C₁₋₆alkyl,        perfluoroC₁₋₆alkoxy, —NR⁵R⁶, —(CH₂)_(n)NR⁵R⁶, —O(CH₂)_(n)OR⁷,        —O(CH₂)_(n)-Het, —O(CH₂)_(n)NR⁵R⁶, —CONR⁵R⁶, —C(O)R⁷,        —CO(CH₂)_(n)NR⁵R⁶, —SO₂R⁷, —SO₂NR⁵R⁶, —NR⁵SO₂R⁷, —NR⁵COR⁷ and        —O(CH₂)_(n)CONR⁵R⁶;    -   R² is hydrogen, C₁₋₆alkyl, halo, cyano or perfluoroC₁₋₆alkyl;    -   R³ is hydrogen or halo;    -   R⁴ is hydrogen, halo, C₁₋₆alkyl or —NR⁵R⁶;    -   R⁵ and R⁶ are independently selected from hydrogen, C₁₋₆alkyl,        perfluoroC₁₋₆alkyl, Het or C₁₋₄alkoxyC₁₋₄alkyl; or R⁵ and R⁶        together with the nitrogen atom to which they are attached form        a 3, 4, 5, 6 or 7-membered saturated or unsaturated ring which        may contain one or more heteroatoms selected from N, S or O, and        wherein the ring may be further substituted by one or more        substituents selected from halo (such as fluoro, chloro, bromo),        cyano, —CF₃, hydroxy, —OCF₃, C₁₋₆alkyl and C₁₋₆alkoxy;    -   R⁷ is hydrogen or C₁₋₆alkyl;    -   Het is a 5 or 6membered C-linked heterocyclyl group which may be        saturated, unsaturated or aromatic, which may contain one or        more heteroatoms selected from N, S or O and which may be        substituted by C₁₋₆alkyl; and    -   n is 1-4.

The term “C₁₋₆alkyl” as used herein, whether on its own or as part of agroup, refers to a straight or branched chain saturated aliphatichydrocarbon radical of 1 to 6 carbon atoms, unless the chain length islimited thereto, including, but not limited to methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl and hexyl.

The term “alkenyl” as a group or part of a group refers to a straight orbranched chain mono- or poly-unsaturated aliphatic hydrocarbon radicalcontaining the specified number(s) of carbon atoms. References to“alkenyl” groups include groups which may be in the E- or Z-form ormixtures thereof.

The term “alkoxy” as a group or part of a group refers to an alkyl etherradical, wherein the term “alkyl” is defined above. Such alkoxy groupsin particular include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy,iso-butoxy, sec-butoxy and tert-butoxy.

The term “perfluoroalkyl” as used herein includes compounds such astrifluoromethyl.

The term “perfluoroalkoxy” as used herein includes compounds such astrifluoromethoxy.

The terms “halo” or “halogen” are used interchangeably herein to meanradicals derived from the elements chlorine, fluorine, iodine andbromine.

The term “heterocyclyl” as used herein includes cyclic groups containing5 to 7 ring-atoms up to 4 of which may be hetero-atoms such as nitrogen,oxygen and sulfur, and may be saturated, unsaturated or aromatic.Examples of heterocyclyl groups are furyl, thienyl, pyrrolyl,pyrrolinyl, pyrrolidinyl, imidazolyl, dioxolanyl, oxazolyl, thiazolyl,imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl,pyrazolidinyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyranyl, pyridyl, piperidinyl, dioxanyl, morpholino,dithianyl, thiomorpholino, pyridazinyl, pyrimidinyl, pyrazinyl,piperazinyl, sulfolanyl, tetrazolyl, triazinyl, azepinyl, oxazepinyl,thiazepinyl, diazepinyl and thiazolinyl. In addition, the termheterocyclyl includes fused heterocyclyl groups, for examplebenzimidazolyl, benzoxazolyl, imidazopyridinyl, benzoxazinyl,benzothiazinyl, oxazolopyridinyl, benzofuranyl, quinolinyl,quinazolinyl, quinoxalinyl, dihydroquinazolinyl, benzothiazolyl,phthalimido, benzofuranyl, benzodiazepinyl, indolyl and isoindolyl.

Preferably X is N.

Preferably R¹ is —NR⁵R⁶, —(CH₂)_(n)NR⁵R⁶, —O(CH₂)_(n)NR⁵R⁶,—O(CH₂)_(n)-Het (preferably imidazolyl), —CONR⁵R⁶, —CO(CH₂)_(n)NR⁵R⁶ or—SO₂R⁷. More preferably R¹ is —NR⁵R⁶, —O(CH₂)_(n)-Het (preferablyimidazolyl) or —CONR⁵R⁶.

Preferably R² is hydrogen, C₁₋₆alkyl, chloro or fluoro. More preferablyR² is hydrogen, methyl, chloro or fluoro. More preferably R² is methyl.

Preferably R³ is hydrogen or fluoro.

Preferably, when X is N, R² is methyl. More preferably when X is N andR² is methyl, R³ is H.

Preferably R⁴ is hydrogen, C₁₋₆alkyl or halo. More preferably, R⁴ ishydrogen, methyl or chloro.

Preferably, R⁵ and R⁶ are independently hydrogen, methyl or Het; or R⁵and R⁶ together with the nitrogen atom to which they are attached form a3, 4, 5, 6 or 7 membered saturated or unsaturated ring which may containone or more heteroatoms selected from N, S or O, and wherein the ringmay be further substituted by one or more substitutents selected fromhalo (such as fluoro, chloro, bromo), cyano, —CF₃, hydroxy, —OCF₃,C₁₋₄alkyl and C₁₋₄alkoxy.

More preferably, R⁵ and R⁶ are independently hydrogen, methyl ortetrahydropyranyl; or R⁵ and R⁶ together with the nitrogen atom to whichthey are attached form a morpholine, pyrrolidine, piperazine ring, eachof which may be substituted by halo (such as fluoro, chloro, bromo),cyano, —CF₃, hydroxy, —OCF₃, C₁₋₄alkyl or C₁₋₄alkoxy.

It will be appreciated that the present invention is intended to includecompounds having any combination of the preferred groups listedhereinbefore.

Preferably

-   -   X is N;    -   R¹ is —NR⁵R⁶, —(CH₂)_(n)NR⁵R⁶, —O(CH₂)_(n)NR⁵R⁶, —O(CH₂)_(n)-Het        (preferably imidazolyl), —CONR⁵R⁶, —CO(CH₂)_(n)NR⁵R⁶ or —SO₂R⁷;    -   R² is hydrogen, C₁₋₆alkyl, chloro or fluoro;    -   R³ is hydrogen or fluoro;    -   R⁴ is hydrogen, C₁₋₆alkyl or halo;    -   R⁵ and R⁶ are independently hydrogen, methyl or Het; or R⁵ and        R⁶ together with the nitrogen atom to which they are attached        form a 3, 4, 5, 6 or 7 membered saturated or unsaturated ring        which may contain one or more heteroatoms selected from N, S or        O, and wherein the ring may be further substituted by one or        more substitutents selected from halo (such as fluoro, chloro,        bromo), cyano, —CF₃, hydroxy, —OCF₃, C₁₋₄alkyl and C₁₋₄alkoxy;    -   R⁷ is hydrogen or C₁₋₆alkyl;    -   Het is a 5 or 6-membered C-linked heterocyclyl group which may        be saturated, unsaturated or aromatic, which may contain one or        more heteroatoms selected from N, S or O and which may be        substituted by C₁₋₆alkyl; and    -   n is 1-4.

Compounds of formula (I) which are of special interest as agents usefulin the treatment or prophylaxis of disorders characterised by theoverexpression of TGF-β are:

-   -   3-[2-(4-methanesulfonyl-phenyl)-pyridin-4-yl]-2-(6-methyl-pyridin-2-yl)-imidazo[1,2-a]pyridine        (Example 6);    -   3-[2-(4-(morpholin-4-yl)-phenyl)-pyridin-4-yl]-2-pyridin-2-yl-imidazo[1,2-a]pyridine        (Example 14);    -   3-{2-[4(4-methylpiperazin-1-yl)-phenyl]-pyridin-4-yl}-2-pyridin-2-yl-imidazo[1,2a]pyridine        (Example 15);    -   2-(6-methyl-pyridin-2-yl)-3-[2-(4-(morpholin-4-ylmethyl)phenyl)-pyridin-4-yl]-imidazo[1,2-a]pyridine        (Example 16);    -   2-(6-methyl-pyridin-2-yl)-3-{2-[4-((morpholin-4-yl)carbonyl)phenyl]-pyridin-4-yl}-imidazo[1,2-a]pyridine        (Example 29);    -   2-(pyridin-2-yl)-3-{2-[4-(2-(pyrrolidin-1-yl)ethoxy)phenyl]-pyridin-4-yl}-imidazo[1,2-a]pyridine        (Example 34);    -   7-methyl-2-(6-methyl-pyridin-2-yl)-3-{2-[4-(2-(pyrrolidin-1-yl)ethoxy)phenyl]-pyridin-4-yl}-imidazo[1,2-a]pyridine        (Example 38);    -   7-methyl-2-(6-methyl-pyridin-2-yl)-3-{2-[4-((1-methyl-imidazol-4-yl)methyloxy)phenyl]-pyridin-4-yl}-imidazo[1,2-a]pyridine        (Example 41); and    -   7-methyl-2-(6-methyl-pyrdin-2-yl)-3-{2-[4(aminocarbonylmethyloxy)phenyl]-pyridin-4-yl}-imidazo[1,2-a]pyridine        (Example 43);    -   and pharmaceutically acceptable salts, solvates and derivatives        thereof.

For the avoidance of doubt, unless otherwise indicated, the termsubstituted means substituted by one or more defined groups. In the casewhere groups may be selected from a number of alternative groups, theselected groups may be the same or different.

For the avoidance of doubt, the term independently means that where morethan one substituent is selected from a number of possible substituents,those substituents may be the same or different.

As used herein the term “pharmaceutically acceptable derivative” meansany pharmaceutically acceptable salt, solvate, ester or amide, or saltor solvate of such ester or amide, of the compound of formula (I), orany other compound which upon administration to the recipient is capableof providing (directly or indirectly) the a compound of formula (I) oran active metabolite or residue thereof, e.g., a prodrug. Preferredpharmaceutically acceptable derivatives according to the invention areany pharmaceutically acceptable salts, solvates or prodrugs.

Suitable pharmaceutically acceptable salts of the compounds of formula(I) include acid salts, for example sodium, potassium, calcium,magnesium and tetraalkylammonium and the like, or mono- or di-basicsalts with the appropriate acid for example organic carboxylic acidssuch as acetic, lactic, tartaric, malic, isethionic, lactobionic andsuccinic acids; organic sulfonic acids such as methanesulfonic,ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids andinorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamicacids and the like. Some of the compounds of this invention may becrystallised or recrystallised from solvents such as aqueous and organicsolvents. In such cases solvates may be formed. This invention includeswithin its scope stoichiometric solvates including hydrates as well ascompounds containing variable amounts of water that may be produced byprocesses such as lyophilisation.

Hereinafter, compounds, their pharmaceutically acceptable salts, theirsolvates and polymorphs, defined in any aspect of the invention (exceptintermediate compounds in chemical processes) are referred to as“compounds of the invention”.

The compounds of the invention may exist in one or more tautomericforms. All tautomers and mixtures thereof are included in the scope ofthe present invention.

Compounds of the invention may exist in the form of optical isomers,e.g. diastereoisomers and mixtures of isomers in all ratios, e.g.racemic mixtures. The invention includes all such forms, in particularthe pure isomeric forms. The different isomeric forms may be separatedor resolved one from the other by conventional methods, or any givenisomer may be obtained by conventional synthetic methods or bystereospecific or asymmetric syntheses.

Since the compounds of the invention are intended for use inpharmaceutical compositions it will readily be understood that they areeach preferably provided in substantially pure form, for example atleast 60% pure, more suitably at least 75% pure and preferably at least85%, especially at least 98% pure (% are on a weight for weight basis).Impure preparations of the compounds may be used for preparing the morepure forms used in the pharmaceutical compositions; these less purepreparations of the compounds should contain at least 1%, more suitablyat least 5% and preferably from 10 to 59% of a compound of theinvention.

Compounds of the invention may be prepared, in known manner in a varietyof ways. In the following reaction schemes and hereafter, unlessotherwise stated R¹ to R⁷, X and n are as defined in the first aspect.These processes form further aspects of the invention.

Throughout the specification, general formulae are designated by Romannumerals (I), (II), (III), (IV) etc. Subsets of these general formulaeare defined as (Ia), (Ib), (Ic) etc . . . (IVa), (IVb), (IVc) etc.

Compounds of formula (I) may be prepared from compounds of formula (II)according to reaction scheme 1, by reacting compounds of formula (II)with compounds of formula (III). Preferred reaction conditions compriseboron coupling of compounds of formula (III) where Y is —B(OH)₂ or4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl cyclic derivative, with acompound of formula (II) in the presence of a suitable palladiumcatalysis (preferably Pd(PPh₃)₄) and a suitable base (preferably sodiumcarbonate) in an inert solvent (preferably 1,2-dimethoxyethane) atelevated temperature.

Compounds of formula (Ia), i.e. compounds of formula (I) where R¹ is—CH₂NR⁶R⁶, may be prepared by reductive amination of compounds offormula (IV) according to reaction scheme 2. Preferred reactionconditions comprise reacting (IV) with HNR⁵R⁶ in the presence ofNaHB(OAc)₃, in a suitable solvent (preferably dichloromethane) at roomtemperature.

Compounds of formula (III) are available from commercial sources or maybe prepared by methods analogous to those described in the Examplessection hereinafter.

Compounds of formula (Ib), i.e. compounds of formula (I) where R¹ is—NR⁵R⁶, may be prepared according to reaction scheme 3 by reactingcompounds of formula (Ic), i.e. compounds of formula (I) where R¹ isbromine, with HNR⁵R⁶ in the presence of a catalyst system preferablytris(dibenzylideneacetone)dipalladium(O) and2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (Binap) in potassiumtert-butoxide in a suitable solvent such as toluene at elevatedtemperature.

Compounds of formula (Id), i.e. compounds of formula (I) where R¹ is—OCH₂CH₂NR⁵R⁸, may be prepared according to reaction scheme 4 byreacting compounds of formula (V) with 1,2-dibromoethane in the presenceof a base preferably potassium carbonate in a suitable solvent, such asacetone, at elevated temperature. Treatment with HNR⁵R⁶ in a suitablesolvent such as tetrahydrofuran at elevated temperature gives (Id).

Compounds of formula (Ie), i.e. compounds of general formula (I) whereR¹ is —CONR⁵R⁶, may be prepared according to reaction scheme 5.Compounds of formula (VI) (where R is methyl or ethyl) are firstlysaponified by heating with sodium hydroxide in methanol, followed byconversion of the resulting carboxylic acid to amide (Ie). Preferredreaction conditions comprise treating the intermediate carboxylic acidwith HNR⁵R⁶ in the presence of HOBT, EDCl and a suitable base such astriethylamine in a suitable solvent such as dimethylformamide at roomtemperature.

Compounds of formula (Ig), i.e. compounds of general formula (I) whereR¹ is —NHSO₂CF₃, may be prepared in two steps according to reactionscheme 6. Firstly the acetyl group is removed from compounds of formula(Ih) by treatment with sodium hydroxide in methanol at elevatedtemperature. The resulting amine is then treated with CF₃SO₂Clpreferably in the presence of a base such as triethylamine in a suitablesolvent such as dichloromethane at room temperature.

It will be apparent to the skilled person that compounds of formula (I)may also be prepared by introducing R¹ before formation of theimidazopyridine. For instance, compounds of formula (Ii), i.e. compoundsof formula (I) where R¹ is morpholine, X is N and R³ is H may beprepared according to reaction scheme 7.

Compounds of formula (II) (see Scheme 1) may be prepared in two stepsaccording to reaction scheme 8. Compounds of formula (VII) are firstlyreacted with a suitable polymer-supported bromine reagent, such aspolymer-supported pyridinium perbromide, in a suitable solvent such asdichloromethane at room temperature. Treatment with a compound offormula (VIII) in a suitable solvent such as ethanol at elevatedtemperature gives compounds of formula (II).

Compounds of formula (VII) may be prepared according to reaction scheme9 by reacting 2-bromo-4-methylpyridine with compounds of formula (IX) inthe presence of a suitable base such as sodium bis(trimethylsilyl)amidein a suitable solvent such as tetrahydrofuran at −78° C. to −30° C.

Further details for the preparation of compounds of formula (I) arefound in the examples.

The compounds of the invention may be prepared singly or as compoundlibraries comprising at least 2, for example 5 to 1,000 compounds, andmore preferably 10 to 100 compounds. Libraries of compounds of theinvention may be prepared by a combinatorial ‘split and mix’ approach orby multiple parallel synthesis using either solution phase or solidphase chemistry, by procedures known to those skilled in the art. Thusaccording to a further aspect there is provided a compound librarycomprising at least 2 compounds of the invention.

Activation of the TGF-β1 axis and expansion of extracellular matrix areearly and persistent contributors to the development and progression ofchronic renal disease and vascular disease. Border W. A., et al, N.Engl. J. Med., 1994; 331(19),1286-92. Further, TGF-β1 plays a role inthe formation of fibronectin and plasminogen activator inhibitor-1,components of sclerotic deposits, through the action of smad3phosphorylation by the TGF-β1 receptor ALK5. Zhang Y., et al, Nature,1998; 394(6696), 909-13; Usui T., et al, Invest. Ophthalmol. Vis. Sci.,1998; 39(11), 1981-9.

Progressive fibrosis in the kidney and cardiovascular system is a majorcause of suffering and death and an important contributor to the cost ofhealth care. TGF-β1 has been implicated in many renal fibroticdisorders. Border W. A., et al, N. Engl. J. Med., 1994; 331(19),1286-92.TGF-β1 is elevated in acute and chronic glomerulonephritis Yoshioka K.,et al, Lab. Invest., 1993; 68(2), 154-63, diabetic nephropathy Yamamoto,T., et al, 1993, PNAS 90, 1814-1818., allograft rejection, HIVnephropathy and angiotensin-induced nephropathy Border W. A., et al, N.Engl. J. Med., 1994; 331(19),1286-92. In these diseases the levels ofTGF-β1 expression coincide with the production of extracellular matrix.Three lines of evidence suggest a causal relationship between TGF-β1 andthe production of matrix. First, normal glomeruli, mesangial cells andnon-renal cells can be induced to produce extracellular-matrix proteinand inhibit protease activity by exogenous TGF-β1 in vitro. Second,neutralizing anti-bodies against TGF-β1 can prevent the accumulation ofextracellular matrix in nephritic rats. Third, TGF-β1 transgenic mice orin vivo transfection of the TGF-β1 gene into normal rat kidneys resultedin the rapid development of glomerulosclerosis. Kopp J. B., et al, Lab.Invest., 1996; 74(6), 991-1003. Thus, inhibition of TGF-β1 activity isindicated as a therapeutic intervention in chronic renal disease.

TGF-β1 and its receptors are increased in injured blood vessels and areindicated in neointima formation following balloon angioplasty SaltisJ., et al, Clin. Exp. Pharmacol. Physiol., 1996; 23(3),193200. Inaddition TGF-β1 is a potent stimulator of smooth muscle cell (“SMC”)migration in vitro and migration of SMC in the arterial wall is acontributing factor in the pathogenesis of atherosclerosis andrestenosis. Moreover, in multivariate analysis of the endothelial cellproducts against total cholesterol, TGF-β receptor ALK5 correlated withtotal cholesterol (P<0.001 ) Blann A. D., et al, Atherosclerosis, 1996;120(1-2), 221-6. Furthermore, SMC derived from human atheroscleroticlesions have an increased ALK5/TGF-β type II receptor ratio. BecauseTGF-β1 is over-expressed in fibroproliferative vascular lesions,receptor-variant cells would be allowed to grow in a slow, butuncontrolled fashion, while overproducing extracellular matrixcomponents McCaffrey T. A., et al, Jr., J. Clin. Invest., 1995; 96(6),2667-75. TGF-β1 was immunolocalized to non-foamy macrophages inatherosclerotic lesions where active matrix synthesis occurs, suggestingthat non-foamy macrophages may participate in modulating matrix geneexpression in atherosclerotic remodelling via a TGF-β-dependentmechanism Therefore, inhibiting the action of TGF-β1 on ALK5 is alsoindicated in atherosclerosis and restenosis.

TGF-β is also indicated in wound repair. Neutralizing antibodies toTGF-β1 have been used in a number of models to illustrate thatinhibition of TGF-β1 signalling is beneficial in restoring functionafter injury by limiting excessive scar formation during the healingprocess. For example, neutralizing antibodies to TGF-β1 and TGF-β2reduced scar formation and improved the cytoarchitecture of theneodermis by reducing the number of monocytes and macrophages as well asdecreasing dermal fibronectin and collagen deposition in rats Shah M.,J. Cell. Sci., 1995,108, 985-1002. Moreover, TGF-β antibodies alsoimprove healing of corneal wounds in rabbits Moller-Pedersen T., Curr.Eye Res., 1998, 17, 736-747, and accelerate wound healing of gastriculcers in the rat, Ernst H., Gut, 1996, 39, 172-175. These data stronglysuggest that limiting the activity of TGF-β would be beneficial in manytissues and suggest that any disease with chronic elevation of TGF-βwould benefit by inhibiting smad2 and smad3 signalling pathways.

TGF-β is also implicated in peritoneal adhesions Saed G. M., et al,Wound Repair Regeneration, November-December 1999, 7(6), 504-510.Therefore, inhibitors of ALK5 would be beneficial in preventingperitoneal and subdermal fibrotic adhesions following surgicalprocedures.

TGF-β is also implicated in photoaging of the skin (see Fisher G J. KangS W. Varani J. Bata-Csorgo Z. Wan Y S. Data S. Voorhees J J., Mechanismsof photoaging and chronological skin ageing, Archives of Dermatology,138(11):1462-1470, November 2002 and Schwartz E. Sapadin A N. Kligman LH. “Ultraviolet B radiation increases steady state mRNA levels forcytokines and integrins in hairless mouse skin-modulation by topicaltretinoin, Archives if Dermatological Research, 290(3):137-144, March1998)

Therefore according to a further aspect, the invention provides the useof a compound defined in the first aspect in the preparation of amedicament for treating or preventing a disease or condition mediated byALK-5 inhibition.

Preferably the disease or condition mediated by ALK-5 inhibition isselected from the list: chronic renal disease, acute renal disease,wound healing, arthritis, osteoporosis, kidney disease, congestive heartfailure, ulcers (including diabetic ulcers, chronic ulcers, gastriculcers, and duodenal ulcers), ocular disorders, corneal wounds, diabeticnephropathy, impaired neurological function, Alzheimer's disease,atherosclerosis, peritoneal and sub-dermal adhesion, any disease whereinfibrosis is a major component, including, but not limited to kidneyfibrosis, lung fibrosis and liver fibrosis, for example, hepatitis Bvirus (HBV), hepatitis C virus (HCV), alcohol-induced hepatitis,haemochromatosis, primary biliary cirrhosis, restenosis, retroperitonealfibrosis, mesenteric fibrosis, endometriosis, keloids, cancer, abnormalbone function, inflammatory disorders, scarring and photaging of theskin.

More preferably the disease or condition mediated by ALK-5 inhibition isfibrosis. Preferably kidney fibrosis.

It will be appreciated that references herein to treatment extend toprophylaxis as well as the treatment of established conditions.

Compounds of the invention may be administered in combination withother, therapeutic agents, for example antiviral agents for liverdiseases, or in combination with ACE inhibitors or angiotensin IIreceptor antagonists for kidney diseases.

The compounds of the invention may be administered in conventionaldosage forms prepared by combining a compound of the invention withstandard pharmaceutical carriers or diluents according to conventionalprocedures well known in the art. These procedures may involve mixing,granulating and compressing or dissolving the ingredients as appropriateto the desired preparation.

The pharmaceutical compositions of the invention may be formulated foradministration by any route, and include those in a form adapted fororal, topical or parenteral administration to mammals including humans.

The compositions may be formulated for administration by any route. Thecompositions may be in the form of tablets, capsules, powders, granules,lozenges, creams or liquid preparations, such as oral or sterileparenteral solutions or suspensions.

The topical formulations of the present invention may be presented as,for instance, ointments, creams or lotions, eye ointments and eye or eardrops, impregnated dressings and aerosols, and may contain appropriateconventional additives such as preservatives, solvents to assist drugpenetration and emollients in ointments and creams.

The formulations may also contain compatible conventional carriers, suchas cream or ointment bases and ethanol or oleyl alcohol for lotions.Such carriers may be present as from about 1% up to about 98% of theformulation. More usually they will form up to about 80% of theformulation.

Tablets and capsules for oral administration may be in unit dosepresentation form, and may contain conventional excipients such asbinding agents, for example syrup, acacia, gelatin, sorbitol,tragacanth, or polyvinylpyrrolidone; fillers, for example lactose,sugar, maize-starch, calcium phosphate, sorbitol or glycine; tablettinglubricants, for example magnesium stearate, talc, polyethylene glycol orsilica; disintegrants, for example potato starch; or acceptable wettingagents such as sodium lauryl sulphate. The tablets may be coatedaccording to methods well known in normal pharmaceutical practice. Oralliquid preparations may be in the form of, for example, aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives, such as suspending agents, for example sorbitol,methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose,carboxymethyl cellulose, aluminium stearate gel or hydrogenated ediblefats, emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample almond oil, oily esters such as glycerine, propylene glycol, orethyl alcohol; preservatives, for example methyl or propylp-hydroxybenzoate or sorbic acid, and, if desired, conventionalflavouring or colouring agents.

Suppositories will contain conventional suppository bases, e.g.cocoa-butter or other glyceride.

For parenteral administration, fluid unit dosage forms are preparedutilising the compound and a sterile vehicle, water being preferred. Thecompound, depending on the vehicle and concentration used, can be eithersuspended or dissolved in the vehicle. In preparing solutions thecompound can be dissolved in water for injection and filter sterilisedbefore filling into a suitable vial or ampoule and sealing.

Advantageously, agents such as a local anaesthetic, preservative andbuffering agents can be dissolved in the vehicle. To enhance thestability, the composition can be frozen after filling into the vial andthe water removed under vacuum. The dry lyophilised powder is thensealed in the vial and an accompanying vial of water for injection maybe supplied to reconstitute the liquid prior to use. Parenteralsuspensions are prepared in substantially the same manner except thatthe compound is suspended in the vehicle instead of being dissolved andsterilisation cannot be accomplished by filtration. The compound can besterilised by exposure to ethylene oxide before suspending in thesterile vehicle. Advantageously, a surfactant or wetting agent isincluded in the composition to facilitate uniform distribution of thecompound.

The compositions may contain from 0.1 % by weight, preferably from10-60% by weight, of the active material, depending on the method ofadministration. Where the compositions comprise dosage units, each unitwill preferably contain from 50-500 mg of the active ingredient. Thedosage as employed for adult human treatment will preferably range from100 to 3000 mg per day, for instance 1500 mg per day depending on theroute and frequency of administration. Such a dosage corresponds to 1.5to 50 mg/kg per day Suitably the dosage is from 5 to 20 mg/kg per day.

It will be recognised by one of skill in the art that the optimalquantity and spacing of individual dosages of a compound of theinvention will be determined by the nature and extent of the conditionbeing treated, the form, route and site of administration, and theparticular mammal being treated, and that such optimums can bedetermined by conventional techniques. It will also be appreciated byone of skill in the art that the optimal course of treatment, i.e., thenumber of doses of a compound of the invention given per day for adefined number of days, can be ascertained by those skilled in the artusing conventional course of treatment determination tests.

No toxicological effects are indicated when a compound of the inventionis administered in the above-mentioned dosage range.

All publications, including, but not limited to, patents and patentapplications cited in this specification, are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

It will be appreciated that the invention includes the following furtheraspects. The preferred embodiments described for the first aspect extendthese further aspects:

-   -   i) a pharmaceutical composition comprising a compound of the        invention and a pharmaceutically acceptable carrier or diluent;    -   ii) a compound of the invention for use as a medicament;    -   iii) a method of treatment or prophylaxis of a disorder selected        from chronic renal disease, acute renal disease, wound healing,        arthritis, osteoporosis, kidney disease, congestive heart        failure, ulcers (including diabetic ulcers, chronic ulcers,        gastric ulcers, and duodenal ulcers), ocular disorders, corneal        wounds, diabetic nephropathy, impaired neurological function,        Alzheimer's disease, atherosclerosis, peritoneal and sub-dermal        adhesion, any disease wherein fibrosis is a major component,        including, but not limited to kidney fibrosis, lung fibrosis and        liver fibrosis, for example, hepatitis B virus (HBV), hepatitis        C virus (HCV), alcohol-induced hepatitis, haemochromatosis,        primary biliary cirrhosis, restenosis, retroperitoneal fibrosis,        mesenteric fibrosis, endometriosis, keloids, cancer, abnormal        bone function, inflammatory disorders, scarring and photoaging        of the skin, in mammals, which comprises administration to the        mammal in need of such treatment, an effective amount of a        compound of the invention; and    -   iv) a combination of a compound of the invention with an ACE        inhibitor or an angiotensin II receptor antagonist.

According to the invention there is provided a compound of formula (I)or a pharmaceutically acceptable salt, solvate or derivative thereof:

wherein X is N or CH;

-   -   R¹ is selected from H, C₁₋₆alkyl, C₁₋₆alkenyl, C₁₋₆alkoxy, halo,        cyano, perfluoro C₁₋₆alkyl, perfluoroC₁₋₆alkoxy, —NR⁵R⁶,        —(CH₂)_(n)R⁵R⁶, —O(CH₂)_(n)OR⁷, —O(CH₂)_(n)NR⁵R⁶, —CONR⁵R⁶,        —CO(CH₂)_(n)NR⁵R⁶, —SO₂R⁷, —SO₂NR⁵R⁶, —NR⁵SO₂R⁷ and —NR⁵COR⁷;    -   R² is selected from H, C₁₋₆alkyl, halo, CN or        perfluoroC₁₋₆alkyl;    -   R³ is selected from H or halo;    -   R⁴ is selected from H, halo, C₁₋₆alkyl or —NR⁵R⁶,    -   R⁵, R⁶ and R⁷ are independently selected from H or C₁₋₆alkyl; or        R⁵ and R⁶ together with the atom to which they are attached form        a 3, 4, 5, 6 or 7-membered saturated or unsaturated ring which        may contain one or more heteroatoms selected from N, S or O, and        wherein the ring may be further substituted by one or more        substituents selected from halo (such as fluoro, chloro, bromo),        —CN, —CF₃, —OH, —OCF₃, C₁₋₆ alkyl and C₁₋₆ alkoxy; and    -   n is 1-4.

The following non-limiting examples illustrate the present invention.

ABBREVIATIONS

-   Binap—2,2′-bis(diphenylphosphino)-1,1′-binaphthyl-   CH₂Cl₂—dichloromethane-   DME—1,2-Dimethoxyethane-   DMF—dimethylformamide-   EDCl—1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride-   EtOH—ethanol-   EtOAc—ethyl acetate-   HOBT—1-hydroxybenzotriazole hydrate-   KMnO₄—potassium permanganate-   NaHB(OAc)₃—sodium triacetoxyborohydride-   NaHMDS—sodium bis(trimethylsilyl)amide-   NaOH—sodium hydroxide-   Na₂SO₄—sodium sulfate-   MeOH—methanol-   THF—tetrahydrofuran-   TEA—triethylamine-   DME—dimethyoxyethane-   Pd₂(dba)₃—tris (dibenzylideneacetone)dipalladium-   Pd(PPh₃)₄—tetrakis(triphenlyphosphine) palladium(0)-   PTS—para-toluene sulfonic acid

Intermediate 1: 3-Chloro-4-fluoro-benzoic acid ethyl ester

To a solution of 3-chloro-4-fluoro-benzoic acid (11.75 g, 67.3 mmol) inEtOH was added PTS (1.2 g) and the resulting mixture was heated underreflux for 2 days. On cooling the mixture was poured into water. Theaqueous phase was basified with a solution of NaOH 1N. The product wasextracted with CH₂Cl₂ and the organic phase was dried over Na₂SO₄ andconcentrated under reduced pressure to give the title compound as an oil(13.08g, 96%); [APCI MS] m/z 203 (MH+).

Intermediate 2: 3,4-Difluoro-benzoic acid ethyl ester

3,4-Difluoro-benzoic acid (11 g, 69.57 mmol) was reacted as describedfor intermediate 1 to afford the title compound as an oil (11.78 g,91%); ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.84 (m, 2H), 7.22 (m, 1H), 4.37(q, 2H), 1.38 (t, 3H).

Intermediate 3: 6-Methyl-pyridine-2-carboxylic acid ethyl ester

6-Methyl-pyridine-2-carboxylic acid (25 g, 182.3 mmol) was reacted asdescribed for intermediate 1 to afford the title compound as an oil(22.9 g, 76.13%); ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.95 (d, 1H), 7.75 (t,1H), 7.35 (d, 1H), 4.5 (q, 2H), 2.7 (s, 3H), 1.45 (t, 3H).

Intermediate 4: 6-Fluoro-pyridine-2-carboxylic acid

To a solution of 2-fluoro-6-methyl-pyridine (2.5 g, 22.5 mmol) in water(170 ml) was added portion-wise KMnO₄ (2 g, 12.65 mmol) and the mixturewas heated to reflux; KMnO₄ (8 g, 50.63 mmol) was added portion-wise andthe mixture was heated under reflux for 3 hours and then cooled. Theprecipitate was filtered and the filtrate was acidified with a solutionof HCl and then concentrated under reduced pressure. The residue wastriturated with hot EtOH, the solid filtered and the filtrate wasconcentrated to dryness under reduced pressure. The title compound wasobtained as a white solid (1.7 g, 53%); m.p. 137° C.

Intermediate 5: 6-Fluoro-pyridine-2-carboxylic acid isopropyl ester

Intermediate 4 (1 g, 7.09 mmol) was added portion-wise to thionylchloride (3 ml) and the mixture was heated under reflux for 3 hours andthen concentrated under reduced pressure. Isopropanol (3 ml) was addedto the residue and the mixture was stirred at room temperature for 5minutes and then concentrated under reduced pressure. The residue wastreated with a saturated aqueous solution of NaHCO₃ and extracted withethyl acetate. The combined organic phases were dried over Na₂SO₄ andconcentrated under reduced pressure. The title compound was obtained asan oil (1.2 g, 93%); [APCI MS] m/z: 184 (MH+).

Intermediate 6: 1-Methyl4-hydroxymethyl-imidazole

To a suspension of 1-methyl-imidazole-4-carboxylic acid (11.4 g, 90mmol) in THF (500 ml) at 0° C., was added drop-wise a solution oflithium aluminium hydride (1M in THF, 117 ml, 117 mmol) and the mixturewas stirred at room temperature overnight and then at 50° C. for 1 hour.Water (3 ml) was added followed by Na₂SO₄ and the mixture was filteredthrough celite™. The filtrate was concentrated under reduced pressure toafford the title compound as a solid (8 g, 78.95%); ¹H NMR (300 MHz,CDCl₃) δ ppm: 7.25 (s, 1H), 6.7 (s, 1H), 5.25 (m, 1H), 4.4 (s, 2H), 3.45(s, 3H).

Intermediate 7: 1-Methyl-4-chloromethyl-imidazole hydrochloride

To a solution of intermediate 6 (5 g, 44.64 mmol) in CH₂Cl₂ (10 ml) at0° C. was added dropwise thionyl chloride (50 ml) and the mixture wasstirred at room temperature overnight and then at reflux for 3 hours.The mixture was concentrated under reduced pressure and the residuetaken up in diethyl ether to give a precipitate. The precipitate wasfiltered and dried to give the title compound (4 g, 53.81 %); ¹H NMR,(300 MHz, DMSO-d₆) δ ppm: 9.25 (s, 1H), 7.8 (s, 1H), 4.95 (s, 2H), 3.9(s, 3H).

Intermediate 8: 4-(Morpholin-4-yl)-bromobenzene

To an ice-cooled solution of 4-phenyl-morpholine (18 g, 110.4 mmol) inethanol (400 ml), was added dropwise bromine (5.95 ml, 115.9 mmol).After addition the mixture was warmed to room temperature and stirredfor 2 hours. The mixture was poured into water and the solution wasbasified with 1N sodium hydroxide solution. The resulting precipitatewas filtered, washed with water and dried. Recrystallisation fromdiisopropyl ether gave the title compound as white crystals (15 g,56.13%); m.p. 126-128° C.

Intermediate 9:N-[4(4,4,5,5-Tetramethyl-[1,3,2]-dioxaborolan-2-yl)-phenyl]-morpholine

To a solution of intermediate 8 (20 g, 82.64 mmol) in dioxane (200 ml)was added 4,4,5,5-tetramethyl-[1,3,2]-dioxaborolane (13.2 ml, 99.17mmol), dichloro bis(triphenylphosphine) palladium (II) (3 g, 4.13 mmol)and triethylamine (34.5 ml, 247.93 mmol) and the mixture was heatedunder reflux for 4 hours. The reaction mixture was cooled, poured intowater and extracted with CH₂Cl₂. The combined organic phases were driedover Na₂SO₄ and concentrated under reduced pressure. The residue waspurified by chromatography on silica gel eluting with CH₂Cl₂to give thetitle compound was obtained as an orange oil which crystallised (19.98g, 83.94%); [APCI MS] m/z 289.07 (MH⁺).

Intermediate 10:4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(tetrahydropyran-4-yl)-benzamide

4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid (70.16 g,0.28 mol) was treated with thionyl chloride (2 vol) and the reactionmixture was stirred at reflux for 2 hours. The mixture was cooled andevaporated to give a residue. The residue was dissolved in toluene andthe mixture was poured into a solution of tetrahydropyran-4-ylamine(34.34 g, 0.339) and triethylamine (79 mL, 0.57 mol) in CH₂Cl₂ at 10° C.The mixture was warmed to room temperature and stirred for 2 days.Addition of water (490 ml) gave a precipitate which was filtered andwashed with EtOAc. Purification by flash chromatography eluting withCH₂Cl₂/MeOH (95:5) gave the title compound as a solid (17.02 g, 18%); ¹HNMR (400 MHz, CDCl₃) δ ppm: 7.85 (d, 2H), 7.72 (d, 2H), 5.98 (m, 1H),4.20 (s, 1H), 3.99 (m, 2H), 3.35 (t, 2H), 2.01 (d, 2H), 1.57 (m, 2H),1.35 (s, 12H).

Intermediate 11:N-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanesulfonamide

To a solution of4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-aniline (5 g, 22.8mmol) in CH₂Cl₂ (20 ml) was added NaHCO₃ (2.3 g, 27.4 mmol) andmethanesulfonyl chloride (13.2 mL, 171 mmol) and the reaction mixturewas stirred at room temperature for 6 days. Water was added and themixture was extracted with CH₂Cl₂. The organic phase was dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas recrystallised from diethyl ether to give the title compound as awhite powder (2.52 g, 37%); ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.78 (d, 2H),7.18 (d, 2H), 6.69 (m, 1H), 3.02 (s, 3H), 1.33 (s, 12H).

Intermediate 12:N-[(4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl)carbonyl]-morpholine

To a solution of4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid (5 g,20.15 mmol) in CH₂Cl₂/DMF (50 ml/5 ml) was added morpholine (2.1 ml,24.2 mmol), HOBT (3.3 g, 24.2 mmol), EDCl (4.65 g, 24.2 mmol) andtriethylamine (4.2 ml, 30.2 mmol) and the reaction mixture was stirredat room temperature for 3 days. Water was added and the product wasextracted with CH₂Cl₂. The combined organic extracts were dried overNa₂SO₄ and concentrated under reduced pressure to give a reside.Trituration of the residue with diisopropyl ether gave the title productas a white solid (4.21 g, 66%); ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.8 (d,2H), 7.4 (d, 2H), 3.7 (m, 4H), 3.55 (m, 2H), 3.35 (m, 2H), 1.3 (s, 12H).

Intermediate 13:1-Ethyl-4-[(4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl)carbonyl]-piperazine

4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid (8.24 g,33.22 mmol) and N-ethylpiperazine (5.1 ml, 39.87 mmol) were reacted asdescribed for intermediate 12 to give, after chromatography on silicagel (CH₂Cl₂/MeOH, 95:5), the title compound (9.64 g, 84%); [APCI MS] m/z345 (MH⁺).

Intermediate 14: 2-[2-Bromo-pyridin-4-yl]-1-pyridin-2-yl-ethanone

To a solution of 2-bromo-4-methyl-pyridine (27 g, 157 mmol) in dry THF(270 ml) was added ethyl picolinate (28.5 g, 188.7 mmol). The resultingmixture was cooled to −78° C. under argon and a solution of sodiumbis-(trimethylsilyl)amide (1 M in THF, 345 ml, 345 mmol) was addeddropwise at −78° C. The reaction mixture was allowed to reach roomtemperature and stirred overnight. The solvent was evaporated underreduced pressure and the residue triturated with diethyl ether. Thesolid was filtered and washed with diethyl ether. The solid was taken-upin saturated NH₄Cl solution and the aqueous phase extracted with ethylacetate. The organic phase was dried over Na₂SO₄ and concentrated togive an orange powder which was washed with pentane to give the titlecompound as a yellow solid (33.97 g); m.p. 111.2° C.

Intermediate 15:2-[2-Bromo-pyridin-4-yl]-1-(6-methyl-pyridin-2-yl)-ethanone

A solution of sodium bis-(trimethylsilyl)amide (2M in THF, 32 ml, 64mmol) was added dropwise at −30° C. to a solution of2-bromo-4-methyl-pyridine (5 g, 29 mmol) in dry THF (70 ml). The mixturewas stirred at −30° C. for 1 hour and then 6-methylpicolinic acid methylester (4.82 g, 32.3 mmol, 1.1 eq) was added. The reaction mixture wasstirred at room temperature overnight. Diethyl ether was added and theresulting solid was filtered and washed with diethyl ether. The solidwas taken up in saturated NH₄Cl solution and the aqueous phase wasextracted with ethyl acetate. The organic layer was dried over Na₂SO₄and concentrated. The resulting orange powder was washed with pentane togive the title compound as a yellow solid (5.84 g, 70%); [APCI MS] m/z292 (MH+).

Intermediate 16:2-(2-Bromo-pyridin-4-yl)-1-(3-chloro-4-fluoro-phenyl)-ethanone

2-Bromo-4-methyl-pyridine (9.2 g, 53.5 mmol) and3-chloro-4-fluoro-benzoic acid ethyl ester (13 g, 64.2 mmol) werereacted as described for intermediate 14 to afford the title compound asan orange solid (17.16 g, 98%); [APCI MS] m/z: 330 (MH+).

Intermediate 17:2-(2-Bromo-pyridin-4-yl)-1-(3,4-difluoro-phenyl)-ethanone

2-Bromo-4-methyl-pyridine (9.056 g, 52.64 mmol) and 3,4-difluoro-benzoicacid ethyl ester (11.75 g, 63.17 mmol) were reacted as described forintermediate 14 to afford the title compound as an ocre solid (14.54 g,88.5%); [APCI MS] m/z: 314 (MH+).

Intermediate 18: 2-(2-Bromo-pyridin-4-yl)-1-(3-chloro-phenyl)-ethanone

2-Bromo-4-methyl-pyridine (7.75 g, 45.1 mmol) andmethyl-3-chlorobenzoate (10 g, 58.6 mmol) were reacted as described forintermediate 14 to afford the title compound as an orange powder (13.02g, 93%); ¹H NMR (300 MHz, CDCl₃) δ ppm: 8.34 (d, 1H), 7.95 (m, 1H), 7.84(d, 1H), 7.59 (d, 1H), 7.46 (d, 1H), 7.41 (d, 1H) 7.13 (d, 1H), 4.24 (s,2H).

Intermediate 19:2-(2-Bromo-pyridin-4-yl)-1-(6-fluoro-pyridin-2-yl)-ethanone

To a solution of 2-bromo-4-methyl-pyridine (2.58 g, 15 mmol) inanhydrous THF (50 ml) at −30° C., was added dropwise NaHMDS (solution 2Min THF, 15 ml, 30 mmol) and the mixture was stirred at −30° C. for 2hours. A solution of intermediate 5 (2.74 g, 15 mmol) in THF (50 ml) wasadded dropwise and the mixture was stirred at −30° C. for 1 hour. Themixture was allowed to reach room temperature and poured into water. Themixture was extracted with EtOAc, the combined organic phases were driedover Na₂SO₄ and the mixture was concentrated under reduced pressure. Theconcentrate was purified by chromatography on silica gel (CH₂Cl₂/MeOH,99:1) to give the title compound as a yellow solid (1.6 g, 36%); [APCIMS] m/z 295 (MH+).

Intermediate 20:2-(2-(4-(Morpholin-4-yl)phenyl)-pyridin-4-yl)-1-(6-methyl-pyridin-2-yl)-ethanone

To a solution of intermediate 15 (3 g, 10.3 mmol) in DME (100 mL) wasadded tetrakis(triphenylphosphine)palladium(0) (1.2 g, 10% mol),intermediate 9 (3.86 g, 13.4 mmol) and Na₂CO₃ (2M, 10.3 ml) and themixture was heated under reflux for 18 hours. The cooled mixture waspoured into water and extracted with CH₂Cl₂. The organic phase waswashed with water, dried over Na₂SO₄ and filtered. Evaporation of thesolvent in vacuo gave a crude oil which was purified by chromatographyon silica gel (CH₂Cl₂/MeOH, 97:3) to give the title compound (3.77 g,98%); [APCI MS] m/z 374.13 (MH+).

Intermediate 21:3-(2-Bromo-pyridin-4-yl)-2-(pyridin-2-yl)-imidazo[1,2-a]pyridine

To a solution of intermediate 14 (5 g, 18.05 mmol) in CH₂Cl₂ (30 ml) wasadded bromine-polymer-supported (11.28 g, 18.05 mmol) and the suspensionwas stirred at room temperature for 5 hours. The suspension wasfiltered, washing through ethanol. The filtrate and washings were addedto 2-aminopyridine (3.4 g, 36.06 mmol) and the mixture heated underreflux for 18 hours. On cooling the mixture was concentrated and theresidue was extracted between water and CH₂Cl₂. The combined organicphases were dried over Na₂SO₄ and evaporated under reduced pressure togive a crude solid which was precipitated from diisopropyl ether toafford the title compound (3.053 g; 48%); m.p 227° C.

Intermediate 22:3-(2-Bromo-pyridin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[1,2-a]pyridine

Intermediate 15 (5 g, 17.18 mmol) and 2-aminopyridine (3.23 g, 34.32mmol) were coupled and treated as described for intermediate 21 toafford the title compound as a brown powder (3.621 g, 58%); ¹H NMR (300MHz, CDCl₃) δ ppm: 8.47 (d, 1H); 8.12 (d, 1H); 7.8 (m, 2H); 7.7 (d, 1H);7.6 (t, 1H); 7.47 (d, 1H); 7.29 (t, 1H); 7.05 (d, 1H); 6.85 (t, 1H);2.39 (s, 3H).

Intermediate 23:3-(2-Bromo-pyridin-4-yl)-2-(3-chloro-4-fluoro-phenyl)-imidazo[1,2-a]pyridine

Intermediate 16 (5 g, 15.22 mmol) and 2-amino-pyridine (2.86 g, 30.44mmol) were coupled and treated as described for intermediate 21 toafford the title compound (3 g, 49%); [APCI MS] m/z 404 (MH+)

Intermediate 24:3-(2-Bromo-pyridin-4-yl)-2-(3,4-difluoro-phenyl)-imidazo[1,2-a]pyridine

Intermediate 17 (5 g, 16 mmol) and 2-aminopyridine (3 g, 32 mmol) werecoupled and treated as described for intermediate 21 to afford, aftercrystallisation from diisopropyl ether, the title compound as a brownpowder (2.95 g, 88%); [APCI MS] m/z 386 (MH+).

Intermediate 25:3-(2-Bromo-pyridin-4-yl)-6-chloro-2-(6-methyl-pyridin-2-yl)-imidazo[1,2-a]pyridine

Intermediate 15 (2 g, 6.87 mmol) and 2-amino-5-chloropyridine (1.77 g,13.75 mmol) were coupled and treated as described for intermediate 21 toafford the title compound as a brown powder (1.152 g, 42%); ¹H NMR (300MHz, CDCl₃) δ ppm: 8.50 (d, 1H), 8.09 (d, 1H), 7.82 (s, 2H), 7.65 (t,2H), 7.45 (d, 1H), 7.27 (d, 1H), 7.08 (d, 1H), 2.39 (s, 3H).

Intermediate 26:3-(2-Bromo-pyridin-4-yl)-7-methyl-2-(6-methyl-pyridin-2-yl)-imidazo[1,2-a]pyridine

Intermediate 15 (2.53 g, 6.87 mmol) and 2-amino-4-picoline (1.49 g,13.75 mmol) were reacted and treated as described for intermediate 21 toafford the title compound as a brown solid (1.43 g, 55%); ¹H NMR (300MHz, CDCl₃) δ ppm: 8.43 (d, 1H), 8.00 (d, 1H), 7.82 (s, 1H), 7.78 (d,1H), 7.60 (t, 1H), 7.44 (m, 2H), 7.05 (d, 1H), 6.70 (d, 1H), 2.43 (s,3H), 2.40 (s, 3H).

Intermediate 27:3-(2-Bromo-pyridin-4-yl)-8-methyl-2-(6-methyl-pyridin-2-yl)-imidazo[1,2-a]pyridine

Intermediate 15 (5 g, 17.24 mmol) and 2-amino-3-picoline (3.73 g, 34.5mmol) were coupled and treated as described for intermediate 21 toafford the title compound as a brown solid (4.08 g, 62%); ¹H NMR (300MHz, CDCl₃) δ ppm: 8.55 (d, 1H), 8 (d, 1H), 7.85 (d, 1H), 7.8 (s, 1H),7.65 (t, 1H), 7.45 (d, 1H), 7.1 (m, 2H), 6.8 (t, 1H), 2.7 (s, 3H), 2.4(s, 3H).

Intermediate 28:3-(2-Bromo-pyridin-4-yl)-2-(3-chloro-phenyl)-imidazo[1,2-a]pyridine

Intermediate 18 (13 g, 42.1 mmol) and 2-amino-pyridine (7.9 g, 2 eq, 84mmol) were coupled and treated as described for intermediate 21 toafford the title compound as a yellow solid (8.45 g, 52%); [APCI MS] m/z384 (MH+).

Intermediate 29:3-(2-Bromo-pyridin-4-yl)-2-(6-fluoro-pyridin-2-yl)-imidazo[1,2-a]pyridine

Intermediate 19 (0.65 g, 2.1 mmol) and 2-aminopyridine (0.42 g, 4.4mmol) were coupled and treated as described for intermediate 21 toafford, after trituration with diisopropyl ether, the title compound asa cream solid (199 mg, 25%); [APCI MS] m/z 369 (MH+).

Intermediate 30:3-(2-(4-Formyl-phenyl)-pyridin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[1,2-a]pyridine

A solution of intermediate 22 (500 mg, 1.37 mmol) in DME (50 ml) wastreated with tetrakis(triphenylphosphine)palladium(O) (158 mg, 10% mol)and stirred at room temperature for 30 min. Aqueous Na₂CO₃ (2M, 4.2 ml)was added to the reaction mixture, followed by 4-formylphenyl boronicacid (267 mg, 1.78 mmol) and the mixture was heated under refluxovernight. The cooled mixture was poured into ice and extracted withCH₂Cl₂. The organic phase was washed with water, dried over Na₂SO₄ andfiltered. Evaporation of the solvent in vacuo gave a crude oil which waspurified by chromatography on silica gel (CH₂Cl₂/MeOH 95:5) to give thetitle compound (310 mg, 58%); ¹H NMR (300 MHz, CDCl₃) δ ppm: 10.08 (s,1H); 8.86 (d, 1H); 8.10-8.20 (m, 4H); 7.98 (d, 1H); 7.83 (d, 1H); 7.75(d, 1H); 7.61 (t, 1H); 7.51 (m, 1H); 7.30 (t, 1H); 7.04 (d, 1H); 6.85(t,1H); 2.31 (s; 3H).

Intermediate 31:3-(2-(4-Formyl-phenyl)-pyridin-4-yl)-2-pyridin-2-yl-imidazo[1,2-a]pyridine

Intermediate 21 (1.2 g, 3.4 mmol) and 4-formylphenyl boronic acid (612mg, 4.1 mmol) were coupled and treated as described for intermediate 30to afford after crystallisation from acetonitrile, the compound as acream powder (1.1 g, 86%); m.p. 216-218° C.; [APCI MS] m/z 377 (MH+).

Intermediate 32:3-(2-(4-Formyl-phenyl)-pyridin-4-yl)-2-(3-chloro-4-fluoro-phenyl)-imidazo[1,2-a]pyridine

Intermediate 23 (1 g, 2.48 mmol) and 4-formylphenyl boronic acid (484mg, 3.22 mmol) were coupled and treated as described for intermediate 30to afford, after purification by chromatography on silica gel(CH₂Cl₂/MeOH 98:2), the title compound as a yellow solid (380 mg, 36%);[APCI MS] m/z 428 (MH+).

Intermediate 33:3(2-(4-Formyl-phenyl)-pyridin-4-yl)-2-(3,4-difluoro-phenyl)-imidazo[1,2-a]pyridine

Intermediate 24 (1 g, 2.6 mmol) and 4-formylphenyl boronic acid (506 mg,3.37 mmol) were coupled and treated as described for intermediate 30 toafford the title compound as a solid (600 mg, 56%); [APCI MS] m/z 412(MH+).

Intermediate 34:6-Chloro-3-(2-(4formyl-phenyl)-pyridin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[1,2-a]pyridine

Intermediate 25 (1.15 g, 2.88 mmol) and 4-formylphenyl boronic acid (563mg, 3.75 mmol) were reacted and treated as described for intermediate 30to afford, after purification by chromatography on silica gel(CH₂Cl₂/MeOH 90:10), the title compound (1.15 g, 93%); [APCI MS] m/z 425(MH+).

Intermediate 35:7-Methyl-3-(2-(4-formyl-phenyl)-pyridin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[1,2-a]pyridine

Intermediate 26 (1.43 g, 3.78 mmol) and 4-formylbenzene boronic acid(738 mg, 4.92 mmol) were coupled and treated as described forintermediate 30 to afford, after purification by flash chromatography onsilica gel (CH₂Cl₂/MeOH 95:5), the title compound as an orange foam (270mg, 18%); [APCI MS] m/z 405 (MH+).

Intermediate 36:8-Methyl-3-(2-(4-formyl-phenyl)-pyridin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[1,2-a]pyridine

Intermediate 27 (1.5 g, 3.97 mmol) and 4-formylphenyl boronic acid(0.773 g, 5.16 mmol) were coupled and treated as described forintermediate 30 to afford the title compound as a cream powder (1.39 g,86%); ¹H NMR (300 MHz, CDCl₃) δ ppm:10.1 (s, 1H), 8.9 (d, 1H), 8.2 (d,2H), 8.15 (s, 1H), 8.1 (d, 1H), 8 (d, 2H), 7.85 (d, 1H), 7.6 (m, 2H),7.1 (m, 2H), 6.8 (t, 1H), 2.8 (s, 3H), 2.4 (s, 3H).

Intermediate 37:3-{2-[4-(Carboxy)-phenyl]-pyridin-4-yl}-2-(6-methyl-pyridin-2-yl)-imidazo[1,2-a]pyridine

Intermediate 22 (2 g, 5.49 mmol) and4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-benzoic acid (2.04 g,8.24 mmol) were coupled and treated as described for intermediate 30 toafford, after trituration with CH₂Cl/diisopropyl ether, the titlecompound (1.4 g, 62.76%); [APCI MS] m/z 407 (MH+).

Intermediate 38:3-(2-(4-Hydroxy-phenyl)-pyridin-4-yl)-2-(pyridin-2-yl)-imidazo[1,2-a]pyridine

Intermediate 21 (1.85 g, 5.27 mmol) and4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-phenol (1.5 g, 6.85mmol) were coupled and treated as described for intermediate 30 toafford, after purification by flash chromatography on silica gel(CH₂Cl₂/MeOH, 98:2 then 95:5 then 93:7), the title compound as a solid(1.4 g, 73%); [APCI MS] m/z=365 (MH+).

Intermediate 39:3-(2-(4-Hydroxy-phenyl)-pyridin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[1,2-a]pyridine

Intermediate 22 (1 g, 2.74 mmol) and4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-phenol (786 mg, 3.57mmol) were coupled and treated as described for intermediate 30 toafford, after purification by chromatography on silica gel (CH₂Cl₂/MeOH90:10), the title compound (470 mg, 45%); [APCI MS] m/z 379 MH⁺.

Intermediate 40:3-(2-(4-Hydroxy-phenyl)-pyridin-4-yl)-2-(3-chloro-phenyl)-imidazo[1,2-a]pyridine

Intermediate 28 (3 g, 7.83 mmol) and4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-phenol (2.24 g, 10.2mmol) were coupled and treated as described for intermediate 30 toafford, after chromatography on silica gel (CH₂Cl₂/MeOH 95:5), the titlecompound (1.6 g, 51%); ¹H NMR (300 MHz, CDCl₃) δ ppm: 9.05 (s, 1H), 8.55(d, 1H), 7.95 (d, 1H), 7.6 (m, 3H), 7.5 (m, 2H), 7.25 (m, 1H), 7.1 (m,4H), 6.7 (m, 3H).

Intermediate 41:8-Methyl-3-(2-(4-hydroxy-phenyl)-pyridin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[1,2-a]pyridine

Intermediate 27 (2.06 g, 5.45 mmol) and4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-phenol (1.56 g, 7.08mmol) were coupled and treated as described for intermediate 30 toafford the title compound as a brown powder (0.865 g, 40%); [APCI MS]m/z 393 (MH⁺).

Intermediate 42:7-Methyl-3-(2-(4-hydroxy-phenyl)-pyridin-4-yl)-2-(6-methyl-pyridin-2-yl)-imidazo[1,2-a]pyridine

Intermediate 26 (1.17 g, 3.1 mmol) and4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-phenol (0.55 g, 4.02mmol) were coupled and treated as described for intermediate 30 toafford the title compound (0.932 g, 77%); [APCI MS] m/z 393 (MH⁺).

Intermediate 43:3-(2-(4-Bromo-phenyl)-pyridin-4-yl)-2-(pyridin-2-yl)-imidazo[1,2-a]pyridine

Intermediate 21 (3 g, 8.55 mmol) and 4-bromophenyl boronic acid(Aldrich, 2.23 g, 11.11 mmol) were coupled and treated as described forintermediate 30 to afford, after chromatography on silicagel(CH₂Cl₂/MeOH 98:2 then 95:5), the title compound as an oil (2.9 g,79.5%); [APCI MS] m/z: 428.2 (MH+).

Intermediate 44:3-{2-[4-(2-Bromo-ethoxy)-phenyl]-pyridin-4-yl}-2-pyridin-2-yl-imidazo[1,2-a]pyridine

To a solution of intermediate 38 (0.38 g, 1.04 mmol) in acetone (20 ml)was added caesium carbonate (0.68 g, 2.08 mmol) and 1,2-dibromoethane(0.9 ml, 10.4 mmol) and the reaction was heated under reflux for 2 days.After cooling, the reaction was filtered and the solvent was removed invacuo. Purification by chromatography on silica gel (CH₂Cl₂/MeOH, 90:10)gave the title compound (140 mg, 28%); ¹H NMR (CDCl₃, 300 MHz) δ ppm:8.78 (d, 1H), 8.49 (d, 1H), 8.14 (d, 1H), 7.93 (m, 4H), 7.72 (t, 2H),7.34 (m, 2H), 7.17 (m, 1H), 7.00 (d, 2H), 6.83 (t, 1H), 4.33 (t, 2H),3.65 (t, 3H).

Intermediate 45:3-{2-[4-(2-Bromo-ethoxy)-phenyl]-pyridin-4-yl}-2-(6-methyl-pyridin-2-yl)-imidazo[1,2-a]pyridine

Intermediate 39 (0.46 g, 1.22 mmol) and 1,2-dibromoethane (2.08 ml,24.32 mmol) were reacted as described for intermediate 44 to afford,after purification by chromatography on silica gel (CH₂Cl₂/MeOH, 95:5),the title compound (0.3 g, 50%); ¹H NMR (CDCl₃, 300 MHz) δ ppm: 8.75 (d,1H), 8.15 (d, 1H), 7.93 (m, 3H), 7.71 (t, 2H), 7.56 (t, 2H), 7.35 (d,1H), 7.26 (m, 1H), 7.00 (m, 3H), 6.82 (t, 1H), 4.33 (t, 2H), 3.65 (t,2H), 2.37 (s, 3H).

Intermediate 46:3-{2-[4-(2-Bromo-ethoxy)-phenyl]-pyridin-4-yl}-2-(6-chloro-phenyl)-imidazo[1,2-a]pyridine

Intermediate 40 (1.6 g, 4 mmol) and 1,2-dibromoethane (4.37 ml, 50 mmol)were reacted and treated as described for intermediate 44 to afford,after purification by chromatography on silica gel (CH₂Cl₂/MeOH, 95:5),the title compound as an orange oil (2.98 g, 100%); [APCI MS] m/z 505(MH⁺).

Intermediate 47:7-Methyl-3-{2-[4-(2-bromo-ethoxy)-phenyl]-pyridin-4-yl}-2-(6-methyl-pyridin-2-yl)-imidazo[1,2-a]pyridine

Intermediate 42 (3.72 g, 9.49 mmol) and 1,2-dibromoethane (8.2 ml, 94.88mmol) were reacted and treated as described for intermediate 44 toafford after purification by chromatography on silica gel (CH₂Cl₂/MeOH,95/5) and trituration with pentane, the title compound as a yellowpowder (1.28 g, 27%); [APCI MS] m/z 500 (MH⁺).

Intermediate 48:8-Methyl-3-{2-[4-(2-bromo-ethoxy)-phenyl]-pyridin-4-yl}-2-(6-methyl-pyridin-2-yl)-imidazo[1,2-a]pyridine

Intermediate 41 (0.865 g, 2.2 mmol) and 1,2-dibromoethane (1.9 ml, 22.06mmol) were reacted and treated as described for intermediate 44 toafford after purification by chromatography on silica gel (CH₂Cl₂/MeOH,95:5), the title compound (0.389 g, 35%); ¹H NMR (CDCl₃, 300 MHz) δ ppm:8.75 (d, 1H), 8.05 (d, 1H), 7.95 (s, 1H), 7.9 (d, 2H), 7.7 (d, 1H), 7.55(t, 1H), 7.35 (d, 1H), 7 (m, 2H), 6.9 (d, 2H), 6.75 (t, 1H), 4.35 (t,2H), 3.65 (t, 2H), 2.75 (s, 3H), 2.35 (s, 3H).

EXAMPLES Example 13-[2-(4-Methoxyphenyl)-pyridin-4-yl]-2-pyridin-2-yl-imidazo[1,2-a]pyridine

A solution of intermediate 21 (0.5 g, 1.42 mmol) in toluene (10 ml) wastreated with tetrakis(triphenylphosphine)palladium(0) (165 mg, 10% mol)and stirred at room temperature for 30 min. Aqueous Na₂CO₃ (2M, 0.6 ml)was added to the reaction mixture followed by 4-methoxyphenyl boronicacid (0.282 g, 1.3 eq, 1.85 mmol) and the mixture was heated underreflux overnight. The cooled mixture was poured into ice and extractedwith toluene. The layers were separated and the organic layer was washedwith water, dried over Na₂SO₄ and filtered. Evaporation of the filtratein vacuo gave a crude oil which was purified by chromatography on silicagel (CH₂Cl₂/MeOH, 90:10) to give the title compound (68 mg, 13%); m.p.222° C.; TOF MS ES⁺ exact mass calculated for C₂₄H₁₈N₄O: 379.1559 (MH+).Found 379.1540 (MH+).

Example 23-[2-(4-methoxy-phenyl)-pyridin-4-yl]-2-(6-methyl-pyridin-2-yl)-imidazo[1,2-a]pyridine

Intermediate 22 (300 mg, 0.82 mmol) and 4-methoxyphenyl boronic acid(162 mg, 1.07 mmol) were coupled and treated as described for example 1to afford, after purification by chromatography on silica gel(CH₂Cl₂/MeOH, 95:5), the title product as a yellow powder (112 mg, 35%);m.p. 174° C.; [APCI MS] m/z 393 (MH⁺).

Example 32-(6-methyl-pyridin-2-yl)-3-[2-(4-trifluoromethoxy-phenyl)-pyridin-4-yl]-imidazo[1,2-a]pyridine

Intermediate 22 (300 mg, 0.82 mmol) and 4-trifluoromethoxybenzeneboronic acid (220 mg, 1.07 mmol) were coupled and treated as describedfor example 1 to afford, after precipitation in pentane, the titleproduct (137 mg, 37%); m.p. 120° C.; [APCI MS] m/z 447 (MH⁺).

Example 43-[2-(4-Cyano-phenyl)-pyridin-4-yl-2-(6-methyl-pyridin-2-yl)-imidazo[1,2-a]pyridine

Intermediate 22 (300 mg, 0.82 mmol) and 4-cyanobenzene boronic acid (157mg, 1.07 mmol) were coupled and treated as described for example 1 toafford, after recrystallisation from EtOAc, the title compound as ayellow powder (31 mg, 10%); m.p 214° C.; [APCI MS] m/z 388 (MH⁺).

Example 53-[2-(4-Methanesulfonyl-phenyl)-pyridin-4-yl]-2-pyridin-2-yl-imidazo[1,2-a]pyridine

Intermediate 23 (1.5 g, 4.3 mmol) and 4-(methanesulfonyl)-phenyl boronicacid (1 g, 5.1 mmol) were coupled and treated as described for example 1to afford, after crystallisation in acetonitrile, the title compound asa pink powder (730 mg, 40.33%); m.p. 242-244° C.; [APCI MS] m/z 427(MH+).

Example 63-[2-(4-Methanesulfonyl-phenyl)-pyridin-4-yl]-2-(6-methyl-pyridin-2-yl)-imidazo[1,2-a]pyridine

Intermediate 22 (300 mg, 0.82 mmol) and 4-(methanesulfonyl)-phenylboronic acid (214 mg, 1.06 mmol) were coupled and treated as describedfor example 1 to afford, after purification by chromatography on silicagel (CH₂Cl₂/MeOH, 95:5), the title compound as a yellow foam (121 mg,33%); [APCI MS] m/z 441 (MH+); ¹H NMR (300 MHz, CDCl₃) δ (ppm) 8.85 (d,1H); 8.2 (d, 1H); 8.14 (d, 1H); 8.09 (m, 3H); 7.82 (d, 1H); 7.74 (d,1H); 7.58 (m, 2H); 7.53 (m, 1H); 7.44(dd, 1H); 7.3 (t, 1H); 7.05 (d,1H); 6.85 (t, 1H); 3.09 (s, 3H); 2.31 (s, 1H).

Example 78-Methyl-2-(6-methyl-pyridin-2-yl)-3-{2-[4-(methylsulfonyl)phenyl]-pyridin-4-yl}-imidazo[1,2-a]pyridine

Intermediate 27 (0.5 g, 1.3 mmol) and 4-(methylsulfonyl)phenyl boronicacid (0.344 g, 1.72 mmol) were coupled and treated as described forexample 1 to afford, after trituration with EtOAc, the title compound asa yellow gummy solid (250 mg, 41%); [APCI MS] m/z 455 (MH⁺); ¹H NMR (300MHz, CDCl₃) δ (ppm) 8.85 (d, 1H), 8.2 (d, 2H), 8.05 (m, 3H), 7.85 (d,1H), 7.5 (m, 3H), 7.1 (m, 2H), 6.8 (t, 1H), 3.1 (s, 3H), 2.75 (s, 3H),2.35 (s, 3H).

Example 83-[2-(4-(Acetyl)phenyl)-pyridin-4-yl]-2-(pyridin-2-yl)-imidazo[1,2-a]pyridine

Intermediate 21 (2.1 g, 5.98 mmol) and 4-(acetyl)phenyl boronic acid(1.27 g, 7.77 mmol) were coupled and treated as described for example 1to afford, after trituration with EtOAc, the title compound as a creamsolid (1.9 g, 81.4%); m.p. 214° C.; [APCI MS] m/z 391.22 (MH⁺).

Example 93-[2-(4-(Methylcarbonylamino)phenyl)-pyridin-4-yl]-2-pyridin-2-yl-imidazo[1,2-a]pyridine

Intermediate 21 (0.3 g, 0.85 mmol) and4′-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)-acetanilide (0.29 g,1.11 mmol) were coupled and treated as described for example 1 to affordthe title compound as a yellow powder (283 mg, 82%); m.p. 133° C.; [APCIMS] m/z 406 (MH+).

Example 103-[2-(4-(methylcarbonylamino)phenyl)-pyridin-4-yl]-2-(6-methyl-pyridin-2-yl)-imidazo[1,2-a]pyridine

Intermediate 22 (3.76 g, 10.32 mmol) and4′-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)-acetanilide (3.5 g,13.42 mmol) were coupled and treated as described for example 1 toafford, after crystallisation from CH₂Cl₂, the title compound as a cremepowder (2.34 g, 54%); m.p. 257° C.; TOF MS ES⁺ exact mass calculated forC₂₆H₂₁N₆O: 420.1824 (MH+). Found 420.1808 (MH⁺).

Example 112-(3-chloro-phenyl)-3-[2-(4-(methanesulfonylamino)phenyl)-pyridin-4-yl]-imidazo[1,2-a]pyridine

Intermediate 28 (300 mg, 0.78 mmol) and intermediate 12 (302 mg, 1.02mmol) were coupled and treated as described for example 1 to afford,after purification by flash chromatography on silica gel (CH₂Cl₂/MeOH,95:5), the title compound as a yellow foam (93 mg, 25%); m.p. 60° C.(become gummy); TOF MS ES⁺ exact mass calculated for C₂₅H₁₉ClN₄O₂S:475.0995 (MH+). Found: 475.0975 (MH+).

Example 122-(6-methyl-pyridin-2-yl)-3-{2-[4-amino-phenyl]-pyridin-4-yl}-imidazo[1,2-a]pyridine

A mixture of example 10 (2.3 g, 5.48 mmol) in MeOH (50 ml) and 1N HCl(50 ml) were stirred at room temperature for 18 hours. The mixture wasthen basified with 1N NaOH and then extracted with CH₂Cl₂. The combinedorganic phases were dried over Na₂SO₄, filtered and concentrated underreduced pressure to give the title compound as a yellow solid (0.79 g,38%); [APCI MS] m/z: 378 (MH⁺); ¹H NMR (300 MHz, CDCl₃) δ ppm: 8.7 (d,1H), 8.1 (d, 1H), 7.85 (m, 3H), 7.7 (d, 1H), 7.6 (d, 1H), 7.45 (t, 1H),7.25 (m, 2H), 7 (d, 1H), 6.8 (t, 1H), 6.7 (d, 2H), 3.85 (m, 2H), 2.4 (s,3H).

Example 132-(6-Methyl-pyridin-2-yl)-3-{2-[4-(trifluoromethylsulfonylamino)phenyl]-pyridin-4-yl}-imidazo[1,2-a]pyridine

To a solution of example 12 (390 mg, 1.03 mmol) in CH₂Cl₂ (10 ml) wereadded trifluoromethanesulfonic anhydride (0.2 ml, 8.55 mmol) andtriethylamine (0.17 ml, 1.24 mmol) and the mixture was stirred at roomtemperature for 3 days. The mixture was poured into water and extractedwith CH₂Cl₂. The organic phase was dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified bychromatography on silica gel eluting with CH₂Cl₂/MeOH (90:10) to givethe title compound as a yellow powder (178 mg, 33.8%); m.p. 135° C.; TOFMS ES⁺ exact mass calculated for C₂₅H₁₈F₃N₅O₂S: 510.1212 (MH⁺). Found:510.1229 (MH⁺).

Example 143-[2-(4-(morpholin-4-yl)-phenyl)-pyridin-4-yl]-2-pyridin-2-yl-imidazo[1,2-a]pyridine

A mixture of intermediate 43 (400 mg, 0.93 mmol), morpholine (1.2 eq,0.1 ml, 1.1 mmol), Pd₂(dba)₃ (0.05 eq, 43 mg, 0.05 mmol), BINAP (0.15eq, 88 mg, 0.14 mmol) and potassium tert-butoxide (1.4 eq, 126 mg, 1.31mmol) in toluene (50 ml) was heated under reflux for 2 hours. Thereaction mixture was extracted between CH₂Cl₂ and water and combinedorganic extracts were dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by chromatography on silicagel eluting with CH₂Cl₂/MeOH (98:2, 95:5 and then 93:7). The resultingoil was crystallised from CH₂Cl₂/pentane to give the title compound as ayellow solid (140 mg, 35%); m.p. 145° C. (become gummy); TOF MS ES⁺exact mass calculated for C₂₇H₂₃N₅O: 434.1981 (MH+). Found 434.1993(MH+).

Example 153-{2-[4-(4-Methylpiperazin-1-yl)-phenyl]-pyridin-4-yl}-2-pyridin-2-yl-imidazo[1,2-a]pyridine

Intermediate 43 (400 mg, 0.94 mmol) and N-methyl-piperazine (0.125 ml,1.2 eq, 1.13 mmol) were coupled and treated as described for example 14to afford, after crystallisation in CH₂Cl₂/diisopropylether, the titlecompound (70 mg, 17%); m.p. 150° C. (become gummy); [APCI MS] m/z 447(MH+).

Example 162-(6-Methyl-pyridin-2-yl)-3-[2-(4-(morpholin-4-ylmethyl)phenyl)-pyridin-4-yl]-imidazo[1,2-a]pyridine

To a solution of intermediate 30 (310 mg, 0.79 mmol) and morpholine (1.5eq, 0.1 ml, 1.2 mmol) in dry dichloroethane (30 ml) was added sodiumtriacetoxyborohydride (1.5 eq, 253 mg, 1.2 mmol) and the mixture stirredfor 3 hours at room temperature. The mixture was basified with 1N NaOHand the aqueous layer was extracted with CH₂Cl₂. The combined organicextracts were dried over Na₂SO₄, filtered and the filtrate wasconcentrated. The concentrate was recrystallised from ethyl acetate togive the title compound as a white powder (194 mg, 53%); m.p. 156° C.;[APCI MS] m/z 462.28 (MH+).

Example 173-[2-(4-(Morpholin-4-yl-methyl)-phenyl)-pyridin-4-yl]-2-pyridin-2-yl-imidazo[1,2-a]pyridine

Intermediate 31 (1.1 g, 2.9 mmol) and morpholine (307 μl, 3.5 mmol) werecoupled and treated as described for example 16 to afford, afterpurification by chromatography on silica gel (CH₂Cl₂/MeOH, 90:10), thetitle compound as a powder (1.1 g, 85%) m.p. 80° C. (degradation); [APCIMS] m/z 448 (MH⁺).

Example 182-(3-Chloro-4-fluoro-phenyl)-3-[2-(4-(morpholin-4-yl-methyl)phenyl)-pyridin-4-yl]-imidazo[1,2-a]pyridine

Intermediate 32 (0.35 g, 0.82 mmol) and morpholine (0.107 ml, 1.5 eq,1.23 mmol) were coupled and treated as described for example 16 toafford, after crystallisation from EtOAc/iPr₂O, the title compound (45mg, 11%); m.p. 189° C.; [APCI MS] m/z 499 (MH+).

Example 192-(3,4-Difluoro-phenyl)-3-[2-(4-(pyrrolidin-1-yl-methyl)phenyl)-pyridin-4-yl]-imidazo[1,2-a]pyridine

Intermediate 33 (0.30 g, 0.73 mmol) and pyrrolidine (0.09 ml, 1.5 eq,1.1 mmol) were coupled and treated as described for example 16 toafford, after crystallisation from CH₂Cl₂/pentane, the title compound asa yellow powder (51 mg, 45%); m.p. 155° C.; TOF MS ES⁺ exact masscalculated for C₂₉H₂₄F₂N₄: 467.2047 (MH+). Found 467.2063 (MH+).

Example 202-(3,4-Difluoro-phenyl)-3-[2-(4-(morpholin-1-yl-methyl)phenyl)-pyridin-4-yl]-imidazo[1,2-a]pyridine

Intermediate 33 (0.30 g, 0.73 mmol) and morpholine (0.095 mL, 1.1 mmol)were coupled and treated as described for example 16 to afford, aftercrystallisation from CH₂Cl₂ /pentane, the title compound as a whitepowder (135 mg, 38%); m.p. 205° C.; TOF MS ES⁺ exact mass calculated forC₂₉H₂₄F₂N₄O: 483.1996 (MH+). Found 483.2030 (MH+).

Example 216-Chloro-2-(6-methyl-pyridin-2-yl)-3-[2-(4-(morpholin-4-yl-methyl)phenyl)-pyridin-4-yl]-imidazo[1,2-a]pyridine

Intermediate 34 (0.40 g, 0.94 mmol) and morpholine (0.123 ml, 1.41 mmol)were coupled and treated as described for example 16 to afford, aftercrystallisation from diethyl ether, the title compound (129 mg, 28%);m.p. 157° C.; [APCI MS] m/z 496 (MH⁺).

Example 227-Methyl-2-(6-methyl-pyridin-2-yl)-3-[2-(4-(morpholin-4-yl-methyl)phenyl)-pyridin-4-yl]-imidazo[1,2-a]pyridine

Intermediate 35 (270 mg, 0.66 mmol) and morpholine (0.09 ml, 1 mmol)were coupled and treated as described for example 16 to afford, aftercrystallisation from EtOAc, the title compound as an orange solid (68mg, 22%); m.p. 188° C.; TOF MS ES⁺ exact mass calculated for C₃₀H₂₉N₅O:476.2450 (MH+). Found: 476.2445 (MH+).

Example 236-Chloro-2-(6-methyl-pyridin-2-yl)-3-[2-(4-(pyrrolidin-1-yl-methyl)phenyl)-pyridin-4-yl]-imidazo[1,2-a]pyridine

Intermediate 34 (0.30 g, 0.7 mmol) and pyrrolidine (0.09 ml, 1.06 mmol)were coupled and treated as described for example 16 to afford, afterpurification by chromatography on silica gel eluting with CH₂Cl₂/MeOH(90:10 then 80:20), the title compound as a white powder (122 mg, 36%);m.p. 134° C.; TOF MS ES⁺ exact mass calculated for C₂₉H₂₆ClN₅: 480.1955(MH+) found 480.1900 (MH+).

Example 248-Methyl-2-(6-methyl-pyridin-2-yl)-3-{2-[4-((morpholin-4-yl)methyl)phenyl]-pyridin-4-yl}-imidazo[1,2-a]pyridine

Intermediate 36 (400 mg, 0.99 mmol) and morpholine (0.13 ml, 1.49 mmol)were coupled and treated as described for example 16 to afford, aftertrituration with CH₂Cl₂/pentane, the title compound as a white solid(198 mg, 42.13%); m.p. 122° C.; [APCI MS] m/z 476 (MH⁺).

Example 258-Methyl-2-(6-methyl-pyridin-2-yl)-3-{2-[4-((pyrrolidin-1-yl)methyl)phenyl]-pyridin-4-yl]-imidazo[1,2-a]pyridine,hydrochloride

To a solution of intermediate 36 (400 mg, 0.99 mmol) in CH₂Cl₂ (20 ml)were added pyrrolidine (0.13 ml, 1.49 mmol) and sodiumtriacetoxyborohydride (315 mg, 1.49 mmol) and the mixture was stirred atroom temperature for 24 hours. The mixture was poured into water andextracted with CH₂Cl₂. The phases were separated and the combinedorganic extracts were dried over Na₂SO₄, filtered and the filtrate wasconcentrated under reduced pressure. The residue was dissolved in CH₂Cl₂and a solution of hydrochloric acid in diethyl ether (1N, 1.3 ml, 1.3mmol) was added. The resulting precipitate was filtered, washed withdiisopropyl ether and dried to give the title compound as a yellow solid(322 mg, 71%); m.p. 197° C.; ¹H NMR (300 MHz, DMSO-d₆) δ ppm: 8.95 (d,1H), 8.45 (m, 2H), 8.2 (d, 2H), 7.95 (t, 1H), 7.8 (d, 2H), 7.75 (m, 3H),7.5 (d, 1H), 7.25 (t, 1H), 4.4 (m, 2H), 3.3 (m, 2H), 3.05 (m, 2H), 2.95(s, 3H), 2.5 (s, 3H), 2.05 (m, 2H), 1.9 (m, 2H).

Example 263-[2-(4-((Tetrahydropyran-4-yl)aminocarbonyl)phenyl)-pyridin-4-yl]-2-pyridin-2-yl-imidazo[1,2-a]pyridine

Intermediate 21 (0.224 g, 0.638 mmol) and intermediate 10 (0.206 g, 0.83mmol) were coupled and treated as described for example 1 to afford,after purification by chromatography on silica gel (CH₂Cl₂/MeOH 90:10),the title compound as a yellow powder (0.057 g, 19%); m.p. 179° C.;[APCI MS] m/z 476 (MH+).

Example 273-[2-(4-((tetrahydropyran-4-yl)aminocarbonyl)phenyl)-pyridin-4-yl]-2-(6-methyl-pyridin-2-yl)-imidazo[1,2-a]pyridine

Intermediate 22 (300 mg, 0.82 mmol) and intermediate 10 (266 mg, 1.07mmol) were coupled and treated as described for example 1 to afford,after purification by chromatography on silica gel (CH₂Cl₂/MeOH, 90:10),the title compound as a yellow powder (37 mg, 9%); m.p. 128° C.; [APCIMS] m/z 490 (MH+).

Example 282-(3-Chloro-phenyl)-3-[2-(4-((tetrahydropyran-4-yl)aminocarbonyl)phenyl)-pyridin-4-yl]-imidazo[1,2-a]pyridine

Intermediate 28 (300 mg, 0.78 mmol) and intermediate 10 (253 mg, 1.02mmol) were coupled and treated as described for example 1 to afford,after purification by preparative plate chromatography on silica gel(CH₂Cl₂/MeOH 90:10), the title compound as a yellow powder (51 mg, 13%);m.p. 234° C.; ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.85 (d, 2H), 7.75 (d, 2H),7.65 to 7.55 (m, 4H), 7.45 to 7.35 (m, 6H), 7.2 (m, 1H), 6 (d, 1H), 4.2(m, 1H), 4 (m, 2H), 3.5 (m, 2H), 2 (m, 2H), 1.6 (m, 2H).

Example 292-(6-Methyl-pyridin-2-yl)-3-{2-[4-((morpholin-4-yl)carbonyl)phenyl]-pyridin-4-yl}-imidazo[1,2-a]pyridine

To a solution of intermediate 37 (500 mg, 1.23 mmol) in DMF (30 ml) wereadded morpholine (0.13 ml, 1.48 mmol), HOBT (200 mg, 1.48 mmol), EDCl(283 mg, 1.48 mmol) and triethylamine (0.2 ml; 1.48 mmol) and themixture was stirred at room temperature overnight. The reaction mixturewas extracted between CH₂Cl₂ and 1N sodium hydroxide solution. Thephases were separated and the organic phase was washed with water, driedover Na₂SO₄, filtered, and the filtrate was concentrated under reducedpressure. The residue was purified by chromatography on silica gel,eluting with CH₂Cl₂/MeOH (95:5) to give (after trituration withdiisopropyl ether) the title compound as a pale yellow solid (147 mg,25.13%); m.p. 110° C.; [APCI MS] m/z 476.33 (MH+).

Example 302-(6-Methyl-pyridin-2-yl)-3-{2-[4-((3-methoxypropylamino)carbonyl)phenyl]-pyridin-4-yl}-imidazo[1,2-a]pyridine

Intermediate 37 (400 mg, 0.98 mmol) and 3-methoxypropylamine (0.11 ml,1.18 mmol) were coupled and treated as described for example 29 toafford, after trituration with CH₂Cl₂/pentane, the title compound as apale yellow solid (210 mg, 44.69 %); m.p. 165° C.; [APCI MS] m/z 478.36(MH⁺).

Example 318-Methyl-2-(6-methyl-pyridin-2-yl)-3-{2-[4-((morpholin-4-yl)carbonyl)phenyl]-pyridin-4-yl}-imidazo[1,2-a]pyridine

Intermediate 27 (500 mg, 1.32 mmol) and intermediate 12 (545 mg, 1.72mmol) were coupled and treated as described for example 1 to afford thetitle compound as a yellow oil (543 mg, 84%); [APCI MS] m/z 490 (MH+).

Example 328-Methyl-2-(6-methyl-pyridin-2-yl)-3-{2-[4-((1-ethyl-piperazin-4-yl)carbonyl)phenyl]-pyridin-4-yl}-imidazo[1,2-a]pyridine

Intermediate 27 (500 mg, 1.32 mmol) and intermediate 13 (591 mg, 1.72mmol) were coupled and treated as described for example 1 to afford thetitle compound (316 mg, 46%); m.p. 212° C.; TOF MS ES⁺ exact masscalculated for C₃₂H₃₂N₆O: 517.2715 (MH⁺). Found: 517.2751(MH⁺).

Example 332-(6-Fluoro-pyridin-2-yl)-3-{2-[4-((morpholiny-4-yl)carbonyl)phenyl]-pyridin-4-yl}-imidazo[1,2-a]pyridine

Intermediate 29 (200 mg, 0.54 mmol) and intermediate 12 (224 mg, 0.7mmol) were coupled and treated as described for example 1 to afford thetitle compound as a white solid (30 mg, 12%); m.p. 191° C.; TOF MS ES⁺exact mass calculated for C₂₈H₂₂N₆O₂F: 480.1836 (MH⁺). Found: 480.1756(MH⁺).

Example 342-(Pyridin-2-yl)-3-{2-[4-(2-(pyrrolidin-1-yl)ethoxy)phenyl]-pyridin-4-yl}-imidazo[1,2-a]pyridine

A solution of intermediate 44 (140 mg, 0.3 mmol) and pyrrolidine (0.75ml, 9 mmol) in EtOH (5 ml) was heated under reflux for 6 days. Aftercooling water was added and the product was extracted with CH₂Cl₂. Theorganic phase was dried over Na₂SO₄, filtered, and the filtrate wasevaporated under reduced pressure. The residue was purified bychromatography on silica gel eluting with CH₂Cl₂/MeOH/TEA (80:20:1%) togive the title compound (13 mg, 10%); [APCI MS] m/z 462 (MH+); ¹H NMR(300 MHz, CDCl₃) δ ppm: 8.75 (d, 1H), 8.5 (d, 1H), 8.15 (d, 1H), 7.9 (m,3H), 7.85 (s, 1H), 7.7 (m, 2H), 7.3 (m, 2H), 7.2 (m, 1H), 7 (d, 2H),6.85 (t, 1H), 4.2 (t, 2H), 3 (t, 2H), 2.75 (m, 4H), 1.85 (m, 4H).

Example 352-(6-Methyl-pyridin-2-yl)-3-{2-[4-(2-(dimethylamino)ethoxy)phenyl]-pyridin-4-yl}-imidazo[1,2-a]pyridine

A solution of intermediate 45 (300 mg, 6.2 mmol) and dimethylamine(solution 40% in water, 2 ml) in THF (2 ml) was stirred at roomtemperature for 18 hours. After cooling water was added and the productwas extracted with CH₂Cl₂. The organic phase was dried over Na₂SO₄,filtered and the solvent was removed under reduced pressure to give thetitle compound as a orange gum (135 mg, 48%); [APCI MS] m/z 450 (MH+);¹H NMR (300 MHz, CDCl₃) δ ppm: 8.8 (d, 1H), 8.2 (d, 1H), 7.95 (m, 3H),7.75 (m, 2H), 7.6 (t, 1H), 7.4 (d, 1H), 7.3 (m, 1H), 7.05 (m, 3H), 6.9(t, 1H), 4.25 (t, 2H), 3 (t, 2H), 2.55 (s, 6H), 2.4 (s, 3H).

Example 362-(3-Chloro-phenyl)-3-{2-[4-(2-(dimethylamino)ethoxy)phenyl]-pyridin-4-yl}-imidazo[1,2-a]pyridine

Intermediate 46 (300 mg, 0.6 mmol) and dimethylamine (solution 40% inwater, 2 ml) were coupled and treated as described for example 35 toafford, after purification by chromatography on silica gel eluting withCH₂Cl₂/MeOH (90:10 then 80:20), the title compound as a yellow gum (98mg, 35%); TOF MS ES⁺ exact mass calculated for C₂₈H₂₅ClN₄O:469.1795(MH+). Found: 469.1723 (MH+); ¹H NMR (300 MHz, CDCl₃) δ ppm: 8.8 (d,1H), 8.1 (d, 1H), 7.9 (d, 2H), 7.8 (s, 1H), 7.7 (m, 2H), 7.45 (d, 1H),7.25 (m, 3H), 7.2 (m, 1H), 7 (d, 2H), 6.85 (t, 1H), 4.35 (t, 2H), 3.25(t, 2H), 2.7 (s, 6H).

Example 372-(3-Chloro-phenyl)-3-{2-[4-(2-(pyrrolidin-1-yl)ethoxy)phenyl]-pyridin-4-yl}-imidazo[1,2-a]pyridine

Intermediate 46 (300 mg, 0.59 mmol) and pyrrolidine (0.5 ml, 5.96 mmol)were coupled and treated as described for example 34 to afford, aftertrituration with pentane, the title compound as a pale yellow solid (80mg, 27.1%); m.p. 298° C.; TOF MS ES⁺ exact mass calculated forC₃₀H₂₇ClN₄O: 495.1952 (MH+). Found: 495.1957(MH+).

Example 387-Methyl-2-(6-methyl-pyridin-2-yl)-3-{2-[4-(2-(pyrrolidin-1-yl)ethoxy)phenyl]-pyridin-4-yl}-imidazo[1,2-a]pyridine

Intermediate 47 (426 mg, 0.85 mmol) and pyrrolidine (0.71 ml, 8.55 mmol)were coupled and treated as described for example 34 to afford, aftertrituration with pentane, the title compound as a pale yellow solid (102mg, 24.4%); m.p. 163° C.; TOF MS ES⁺ exact mass calculated forC₃₁H₃₁N₅O: 490.2607 (MH⁺). Found: 490.2600 (MH⁺).

Example 397-Methyl-2-(6-methyl-pyridin-2-yl)-3-{2-[4-(2-(morpholin-4-yl)ethoxy)phenyl]-pyridin-4-yl}-imidazo[1,2-a]pyridine

Intermediate 47 (426 mg, 0.85 mmol) and morpholine (0.74 ml, 8.55 mmol)were coupled and treated as described for example 34 to afford the titlecompound as an orange foam (357 mg, 82.64%); TOF MS ES⁺ exact masscalculated for C₃₁H₃₁N₅O₂ 506.2556 (MH⁺). Found: 506.2534 (MH⁺); ¹H NMR(300 MHz, CDCl₃) δ ppm: 8.8 (d, 1H), 8.05 (d, 1H), 7.9 (m, 3H), 7.7 (d,1H), 7.6 (t, 1H), 7.5 (s, 1H), 7.35 (d, 1H), 7 (m, 3H), 6.7 (d, 1H), 4.2(t, 2H), 3.8 (m, 4H), 2.85 (t, 2H), 2.6 (m, 4H), 2.45 (s, 3H), 2.4 (s,3H).

Example 408-Methyl-2-(6-methyl-pyridin-2-yl)-3-{2-[4-(2-(pyrrolidin-1-yl)ethoxy))phenyl]-pyridin-4-yl}-imidazo[1,2-a]pyridine

Intermediate 48 (389 mg, 0.78 mmol) and pyrrolidine (0.65 ml, 7.8 mmol)were coupled and treated as described for example 34 to afford the titlecompound as a gummy solid (160 mg, 41.9%); [APCI MS] m/z 490 (MH+); ¹HNMR (300 MHz, CDCl₃) δ ppm: 8.75 (d, 1H), 8.05 (d, 1H), 7.9 (m, 3H), 7.7(d, 1H), 7.55 (t, 1H), 7.3 (d, 1H), 7.05 (m, 2H), 6.95 (d, 2H), 6.7 (t,1H), 4.25 (t, 2H), 3.05 (t, 2H), 2.9 (m, 4H), 2.7 (s, 3H), 2.4 (s, 3H),1.95(m, 4H).

Example 417-Methyl-2-(6-methyl-pyridin-2-yl)-3-{2-[4-((1-methyl-imidazol-4-yl)methyloxy)phenyl]-pyridin-4-yl}-imidazo[1,2-a]pyridine

To a solution of intermediate 42 (0.4 g, 1.02 mmol) in DMF (20 ml) wasadded portionwise sodium hydride (60% in mineral oil, 101 mg, 2.55 mmol)and the mixture was stirred at room temperature for 20 minutes.Intermediate 7 (173 mg, 1.32 mmol) was then added and the mixture washeated at 60° C. for 3 days. The reaction mixture was poured into waterand extracted with CH₂Cl₂ The combined organic extracts were separated,dried over Na₂SO₄, filtered and the filtrate was concentrated underreduced pressure. The residue was purified by chromatography on silicagel eluting with CH₂Cl₂/MeOH (90:10), to give (after trituration withdiisopropyl ether), the title compound as a yellow solid (130 mg, 26%);m.p. 217° C.; TOF MS ES⁺ exact mass calculated for C₃₀H₂₆N₆O: 487.2246(MH⁺). Found: 487.2247 (MH⁺).

Example 422-(6-Methyl-pyridin-2-yl)-3-{2-[4-((1-methyl-imidazol-4-yl)methyloxy)phenyl]-pyridin-4-yl}-imidazo[1,2-a]pyridine

Intermediate 39 (400 mg, 1.06 mmol) and intermediate 7 (212 mg, 1.27mmol) were coupled and treated as described for example 41 to afford,after trituration with diisopropyl ether, the title compound as a whitesolid (200 mg, 40%); m.p. 120° C.; [APCI MS] m/z 473 (MH+).

Example 437-Methyl-2-(6methyl-pyridin-2-yl)-3-{2-[4(aminocarbonylmethyloxy)phenyl]-pyridin-4-yl}-imidazo[1,2-a]pyridine

To a solution of intermediate 42 (500 mg, 1.27 mmol) in acetone (25 ml)were added caesium carbonate (623 mg, 1.91 mmol) and bromoacetamide (264mg, 1.91 mmol) and the mixture was heated under reflux for 48 hours. Oncooling, the reaction mixture was extracted between water and CH₂Cl₂.The layers were separated and the combined organic layers were driedover Na₂SO₄, filtered and the filtrate was concentrated under reducedpressure. The residue was purified by chromatography on silica geleluting with CH₂Cl₂/MeOH (95:5), to give (after trituration withpentane/ethyl acetate), the title compound (133 mg, 23%); m.p. 213° C.;[APCI MS] m/z 450 MH⁺.

Example 448-Methyl-2-(6-methyl-pyridin-2-yl)-3-{2-[4-(aminocarbonylmethyloxyl)phenyl]-pyridin-4-yl}-imidazo[1,2-a]pyridine

Intermediate 41 (0.5 g, 1.27 mmol) and bromoacetamide (0.264 g, 1.91mmol) were coupled and treated as described for example 43 to afford,after trituration with diisopropyl ether, the title compound (0.08 g,14%); m.p. 183° C.; [APCI MS] m/z 450 (MH+).

Example 452-(6-Methyl-pyridin-2-yl)-3-{2-[4-(morpholin-4-yl)phenyl]-pyridin-4-yl}-imidazo[1,2-a]pyridine

To a solution of intermediate 20 (3 g, 8.04 mmol) in CH₂Cl₂ (80 ml) wasadded bromine-polymer supported (5.03 g, 8.04 mmol) and the suspensionwas stirred at room temperature for 3 hours. The suspension wasfiltered, washing the resin with ethanol. 2-Aminopyridine (1.51 g, 16.08mmol) was added to the combined filtrate and washings and the mixturewas heated at reflux for 18 hours. On cooling, the residue was extractedbetween water and CH₂Cl₂. The combined organic phases were dried overNa₂SO₄, filtered and the filtrate was concentrated under reducedpressure. The concentrate was purified by chromatography on silica gel(eluting with CH₂Cl₂/MeOH, 98:2 then 95:5) to give (after triturationwith diisopropyl ether, the title compound (1.2 g; 33.38%); m.p. 190°C.; TOF MS ES⁺ exact mass calculated for C₂₈H₂₅N₅O: 448.2137(MH⁺).Found: 448.2081 (MH⁺).

Example 467-Methyl-2-(6-methyl-pyridin-2-yl)-3-{2-[4-(morpholin-4-yl)phenyl]-pyridin-4-yl}-imidazo[1,2-a]pyridine

Intermediate 20 (1.27 g, 3.4 mmol) was reacted as described for example45, to afford after trituration with diisopropyl ether, the titlecompound (0.6 g, 38.22%); m.p. 208° C.; TOF MS ES⁺ exact mass calculatedfor C₂₉H₂₇N₅O: 462.2294(MH⁺). Found 462.2263 (MH⁺).

Biology

The biological activity of the compounds of the invention may beassessed using the following assays:

Assay 1 (Cellular Transcriptional Assay)

The potential for compounds of the invention to inhibit TGF-β signallingmay be demonstrated, for example, using the following in vitro assay.

The assay was performed in HepG2 cells stably transfected with the PAI-1promoter (known to be a strong TGF-β responsive promoter) linked to aluciferase (firefly) reporter gene. The compounds were selected on theirability to inhibit luciferase activity in cells exposed to TGF-β. Inaddition, cells were transfected with a second luciferase (Renilla) genewhich was not driven by a TGF-β responsive promoter and was used as atoxicity control.

96 well microplates were seeded, using a multidrop apparatus, with thestably transfected cell line at a concentration of 35000 cells per wellin 200 μl of serum-containing medium. These plates were placed in a cellincubator.

18 to 24 hours later (Day 2), cell-incubation procedure was launched.Cells were incubated with TGF-β and a candidate compound atconcentrations in the range 50 nM to 10 μM (final concentration of DMSO1%). The final concentration of TGF-β (rhTGFβ-1) used in the test was 1ng/mL. Cells were incubated with a candidate compound 15-30 mins priorto the addition of TGF-β. The final volume of the test reaction was 150μl. Each well contained only one candidate compound and its effect onthe PAI-1 promoter was monitored.

Columns 11 and 12 were employed as controls. Column 11 contained 8 wellsin which the cells were incubated in the presence of TGF-β, without acandidate compound. Column 11 was used to determine the ‘reference TGF-βinduced firefly luciferase value’ against which values measured in thetest wells (to quantify inhibitory activity) were compared. In wells A12to D12, cells were grown in medium without TGF-β. The firefly luciferasevalues obtained from these positions are representative of the ‘basalfirefly luciferase activity’. In wells E12 to H12, cells were incubatedin the presence of TGF-β and 500 μM CPO (Cyclopentenone, Sigma), a celltoxic compound The toxicity was revealed by decreased firefly andrenilla luciferase activities (around 50% of those obtained in column11).

12 to 18 hours later (day 3), the luciferase quantification procedurewas launched. The following reactions were performed using reagentsobtained from a Dual Luciferase Assay Kit (Promega). Cells were washedand lysed with the addition of 10 μl of passive lysis buffer (Promega).Following agitation (15 to 30 mins), luciferase activities of the plateswere read in a dual-injector luminometer (BMG lumistar). For thispurpose, 50 μl of luciferase assay reagent and 50 μl of ‘Stop & Glo’buffer were injected sequentially to quantify the activities of bothluciferases. Data obtained from the measurements were processed andanalysed using suitable software. The mean Luciferase activity valueobtained in wells A11 to H11 (Column 11, TGF-βonly) was considered torepresent 100% and values obtained in wells A12 to D12 (cells in mediumalone) gave a basal level (0%). For each of the compounds tested, aconcentration response curve was constructed from which an IC₅₀ valuewas determined graphically.

Assay 2 (Alk5 Fluorescence Polarization Assay)

Kinase inhibitor compounds conjugated to fluorophores, can be used asfluorescent ligands to monitor ATP competitive binding of othercompounds to a given kinase. The increase in depolarization of planepolarized light, caused by release of the bound ligand into solution, ismeasured as a polarization/anisotropy value. This protocol details theuse of a rhodamine green-labelled ligand for assays using recombinantGST-ALK5 (residues 198-503).

Assay buffer components: 62.5 mM Hepes pH 7.5 (Sigma H-4034), 1 mM DTT(Sigma D-0632), 12.5 mM MgCl₂ (Sigma M-9272), 1.25 mM CHAPS (SigmaC-3023).

Protocol: Solid compound stocks were dissolved in 100% DMSO to aconcentration of I mM and transferred into column 1, rows A-H of a96-well, U bottom, polypropylene plate (Costar #3365) to make a compoundplate. The compounds were serially diluted (3-fold in 100% DMSO) acrossthe plate to column 11 to yield 11 concentrations for each testcompound. Column 12 contained only DMSO. A Rapidplate™-96 was used totransfer 1 μl of sample from each well into a 96-well, black, U-bottom,non-treated plate (Costar #3792) to create an assay plate.

ALK5 was added to assay buffer containing the above components and 1 nMof the rhodamine green-labelled ligand so that the final ALK5concentration was 10 nM based on active site titration of the enzyme.The enzyme/ligand reagent (39 μl) was added to each well of thepreviously prepared assay plates. A control compound (1 μl) was added tocolumn 12, rows E-H for the low control values. The plates were readimmediately on a LJL Acquest fluorescence reader (Molecular Devices,serial number AQ1048) with excitation, emission, and dichroic filters of485 nm, 530 nm, and 505 nm, respectively. The fluorescence polarizationfor each well was calculated by the Acquest reader and then importedinto curve fitting software for construction of concentration responsecurves. The normalized response was determined relative to the highcontrols (1 μl DMSO in column 12, rows A-D) and the low controls (1 μlof control compound in column 12, rows E-H). An IC₅₀ value was thencalculated for each compound.

Using the above assays all Examples of the invention show ALK5 receptormodulator activity (having IC₅₀ values in the range of 1 to 200 nM) andTGF-β cellular activity (having IC₅₀ values in the range of 0.001 to 10μM).

3-[2-(4-Methanesulfonyl-phenyl)-pyridin-4-yl]-2-(6-methyl-pyridin-2-yl)-imidazo[1,2-a]pyridine(Example 6) showed an ALK5 receptor modulator activity of 11 nM andTGF-β cellular activity of 125 nM.

7-Methyl-2-(6-methyl-pyridin-2-yl)-3-{2-[4-(2-(pyrrolidin-1-yl)ethoxy)phenyl]-pyridin-4-yl}-imidazo[1,2-a]pyridine(Example 38) showed an ALK5 receptor modulator activity of 15 nM andTGF-β cellular activity of 127 nM.

1. A compound of formula (I), a pharmaceutically acceptable salt,solvate or derivative thereof:

wherein X is N or CH; R¹ is selected from hydrogen, C₁₋₆alkyl,C₁₋₆alkenyl, C₁₋₆alkoxy, halo, cyano, perfluoro C₁₋₆alkyl,perfluoroC₁₋₆alkoxy, —NR⁵R⁶, —(CH₂)_(n)NR⁵R⁶, —O(CH₂)_(n)OR⁷,—O(CH₂)_(n)-Het, —O(CH₂)_(n)NR⁵R⁶, —CONR⁵R⁶, —C(O)R⁷, —CO(CH₂)_(n)NR⁵R⁶,—SO₂R⁷, —SO₂NR⁵R⁶, —NR⁵SO₂R⁷, —NR⁵COR⁷ and —O(CH₂)_(n)CONR⁵R⁶; R² ishydrogen, C₁₋₄alkyl, halo, cyano or perfluoroC₁₋₆alkyl; R³ is hydrogenor halo; R⁴ is hydrogen, halo, C₁₋₆alkyl or —NR⁵R⁶; R⁵ and R⁶ areindependently selected from hydrogen, C₁₋₆alkyl, perfluoroC₁₋₆alkyl, Hetor C₁₋₄alkoxyC₁₋₄alkyl; or R⁵ and R⁶ together with the nitrogen atom towhich they are attached form a 3, 4, 5, 6 or 7-membered saturated orunsaturated ring which may contain one or more heteroatoms selected fromN, S or O, and wherein the ring may be further substituted by one ormore substituents selected from halo (such as fluoro, chloro, bromo),cyano, —CF₃, hydroxy, —OCF₃, C₁₋₆alkyl and C₁₋₆alkoxy; R⁷ is hydrogen orC₁₋₆alkyl; Het is a 5 or 6-membered C-linked heterocyclyl group whichmay be saturated, unsaturated or aromatic, which may contain one or moreheteroatoms selected from N, S or O and which may be substituted byC₁₋₆alkyl; and n is 1-4.
 2. A compound according to claim 1 wherein X isN.
 3. A compound according to claim 1 wherein R¹ is —NR⁵R⁶,—(CH₂)_(n)NR⁵R⁶, —O(CH₂)_(n)NR⁵R⁶, —O(CH₂)_(n)-Het, —CONR⁵R⁶,—CO(CH₂)_(n)NR⁵R⁶ or —SO₂R⁷.
 4. A compound according to claim 1 whereinR² is hydrogen, C₁₋₆alkyl, chloro or fluoro.
 5. A compound according toclaim 1 wherein R³ is hydrogen or fluoro.
 6. A compound according toclaim 1 wherein when X is N, R² is methyl.
 7. A compound according toclaim 1 wherein when X is N and R² is methyl, R³ is hydrogen.
 8. Acompound according claim 1 wherein R⁴ is hydrogen, C₁₋₆alkyl or halo. 9.A compound according to claim 1 wherein R⁵ and R⁶ are independentlyhydrogen, methyl or Het; or R⁵ and R⁶ together with the nitrogen atom towhich they are attached form a 3, 4, 5, 6 or 7 membered saturated orunsaturated ring which may contain one or more heteroatoms selected fromN, S or O, and wherein the ring may be further substituted by one ormore substitutents selected from halo (such as fluoro, chloro, bromo),cyano, —CF₃, hydroxy, —OCF₃, C₁₋₄alkyl and C₁₋₄alkoxy.
 10. A compoundaccording to claim 1 wherein R⁵ and R⁶ are independently hydrogen,methyl or tetrahydropyranyl; or R⁵ and R⁶ together with the nitrogenatom to which they are attached form a morpholine, pyrrolidine,piperazine ring, each of which may be substituted by halo (such asfluoro, chloro, bromo), cyano, —CF₃, hydroxy, —OCF₃, C₁₋₄alkyl orC₁₋₄alkoxy.
 11. A compound according to claim 1 wherein X is N; R¹ is—NR⁵R⁶, —(CH₂)_(n)NR⁵R⁶, —O(CH₂)_(n)NR⁵R⁶, —O(CH₂)_(n)-Het, —CONR⁵R⁶,—CO(CH₂)_(n)NR⁵R⁶ or —SO₂R⁷; R² is hydrogen, C₁₋₆alkyl, chloro orfluoro; R³ is hydrogen or fluoro; R⁴ is hydrogen, C₁₋₆alkyl or halo; R⁵and R⁶ are independently hydrogen, methyl or Het; or R⁵ and R⁶ togetherwith the nitrogen atom to which they are attached form a 3, 4, 5, 6 or 7membered saturated or unsaturated ring which may contain one or moreheteroatoms selected from N, S or O, and wherein the ring may be furthersubstituted by one or more substitutents selected from halo (such asfluoro, chloro, bromo), cyano, —CF₃, hydroxy, —OCF₃, C₁₋₄alkyl andC₁₋₄alkoxy; R⁷ is hydrogen or C₁₋₆alkyl; Het is a 5 or 6-memberedC-linked heterocyclyl group which may be saturated, unsaturated oraromatic, which may contain one or more heteroatoms selected from N, Sor O and which may be substituted by C₁₋₄ alkyl; and n is 1-4.
 12. Acompound according to claim 1 selected from the list:3-[2-(4-methanesulfonyl-phenyl)-pyridin-4-yl]-2-(6-methyl-pyridin-2-yl)-imidazo[1,2-a]pyridine(Example 6);3-[2-(4-(morpholin-4-yl)-phenyl)-pyridin-4-yl]-2-pyridin-2-yl-imidazo[1,2-a]pyridine(Example 14);3-{2-[4-(4-methylpiperazin-1-yl)-phenyl]-pyridin-4-yl}-2-pyridin-2-yl-imidazo[1,2-a]pyridine(Example 15);2-(6-methyl-pyridin-2-yl)-3-[2-(4-(morpholin-4-ylmethyl)phenyl)-pyridin-4-yl]-imidazo[1,2-a]pyridine(Example 16);2-(6-methyl-pyridin-2-yl)-3-{2-[4-((morpholin-4-yl)carbonyl)phenyl]-pyridin-4-yl}-imidazo[1,2-a]pyridine(Example 29);2-(pyridin-2-yl)-3-{2-[4-(2-(pyrrolidin-1-yl)ethoxy)phenyl]-pyridin-4-yl}-imidazo[1,2-a]pyridine(Example 34);7-methyl-2-(6-methyl-pyridin-2-yl)-3-{2-[4-(2-(pyrrolidin-1-yl)ethoxy)phenyl]-pyridin-4-yl}-imidazo[1,2-a]pyridine(Example 38);7-methyl-2-(6-methyl-pyridin-2-yl)-3-{2-[4-((1-methyl-imidazol-4-yl)methyloxy)phenyl]-pyridin-4-yl}-imidazo[1,2-a]pyridine(Example 41); and7-methyl-2-(6-methyl-pyridin-2-yl)-3-{2-[4(aminocarbonylmethyloxy)phenyl]-pyridin-4-yl}-imidazo[1,2-a]pyridine(Example 43); and pharmaceutically acceptable salts, solvates andderivatives thereof.
 13. A pharmaceutical composition comprising acompound defined in claim 1 and a pharmaceutically acceptable carrier ordiluent. 14-17. (canceled)
 18. A method of treatment or prophylaxis of adisorder mediated by the ALK5 receptor in mammals, wherein the disorderis selected from chronic renal disease, acute renal disease, woundhealing, arthritis, osteoporosis, kidney disease, congestive heartfailure, ulcers, ocular disorders, corneal wounds, diabetic nephropathy,impaired neurological function, Alzheimer's disease, atherosclerosis,peritoneal and sub-dermal adhesion, any disease wherein fibrosis is amajor component, including, but not limited to lung fibrosis, kidneyfibrosis, liver fibrosis [for example, hepatitis B virus (HBV),hepatitis C virus (HCV)], alcohol induced hepatitis, retroperitonealfibrosis, mesenteric fibrosis, haemochromatosis and primary biliarycirrhosis, endometriosis, keloids and restenosis comprisingadministering to a mammal in need thereof a compound according to claim1.